[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD (2019) Jemal A (2019) Cancer statistics. CA Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551

    Article  PubMed  Google Scholar 

  3. Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, Neale RE, Tempero M, Tuveson DA, Hruban RH, Neoptolemos JP (2016) Pancreatic cancer. Nat Rev Dis Primers 2:16022. https://doi.org/10.1038/nrdp.2016.22

    Article  PubMed  Google Scholar 

  4. Konstantinidis IT, Warshaw AL, Allen JN, Blaszkowsky LS, Castillo CF, Deshpande V, Hong TS, Kwak EL, Lauwers GY, Ryan DP, Wargo JA, Lillemoe KD, Ferrone CR (2013) Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a “true” R0 resection? Ann Surg 257(4):731–736. https://doi.org/10.1097/SLA.0b013e318263da2f

    Article  PubMed  Google Scholar 

  5. Mizrahi JD, Surana R, Valle JW, Shroff RT (2020) Pancreatic cancer. The Lancet 395(10242):2008–2020. https://doi.org/10.1016/s0140-6736(20)30974-0

    Article  CAS  Google Scholar 

  6. Kunovsky L, Tesarikova P, Kala Z, Kroupa R, Kysela P, Dolina J, Trna J (2018) The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterol Hepatol 2018:5389820. https://doi.org/10.1155/2018/5389820

    Article  PubMed  PubMed Central  Google Scholar 

  7. Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH (2018) Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 15(6):333–348. https://doi.org/10.1038/s41575-018-0005-x

    Article  PubMed  Google Scholar 

  8. Seppanen H, Juuti A, Mustonen H, Haapamaki C, Nordling S, Carpelan-Holmstrom M, Siren J, Luettges J, Haglund C, Kiviluoto T (2017) The Results of Pancreatic Resections and Long-Term Survival for Pancreatic Ductal Adenocarcinoma: A Single-Institution Experience. Scand J Surg 106(1):54–61. https://doi.org/10.1177/1457496916645963

    Article  CAS  PubMed  Google Scholar 

  9. Valle S, Martin-Hijano L, Alcala S, Alonso-Nocelo M, Sainz B Jr (2018) The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer. Cancers (Basel). https://doi.org/10.3390/cancers10020033

    Article  Google Scholar 

  10. Zeng S, Pottler M, Lan B, Grutzmann R, Pilarsky C, Yang H (2019) Chemoresistance in pancreatic cancer. Int J Mol Sci. https://doi.org/10.3390/ijms20184504

    Article  PubMed  PubMed Central  Google Scholar 

  11. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413. https://doi.org/10.1200/JCO.1997.15.6.2403

    Article  CAS  PubMed  Google Scholar 

  12. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. https://doi.org/10.1056/NEJMoa1304369

    Article  CAS  Google Scholar 

  13. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of U, Intergroup P (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. https://doi.org/10.1056/NEJMoa1011923

    Article  Google Scholar 

  14. Faubert B, Solmonson A, DeBerardinis RJ (2020) Metabolic reprogramming and cancer progression. Science. https://doi.org/10.1126/science.aaw5473

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, Lau AN, Ji BW, Dixit PD, Hosios AM, Muir A, Chin CR, Freinkman E, Jacks T, Wolpin BM, Vitkup D, Vander Heiden MG (2016) Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353(6304):1161–1165. https://doi.org/10.1126/science.aaf5171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314. https://doi.org/10.1126/science.123.3191.309

    Article  CAS  PubMed  Google Scholar 

  17. Warburg O, Wind F, Negelein E (1927) The Metabolism of Tumors in the Body. J Gen Physiol 8(6):519–530. https://doi.org/10.1085/jgp.8.6.519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899. https://doi.org/10.1038/nrc1478

    Article  CAS  PubMed  Google Scholar 

  19. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, Burga LN, Xie J, Jurczak MJ, DePinho RA, Clish CB, Jacks T, Kibbey RG, Wulf GM, Di Vizio D, Mills GB, Cantley LC, Vander Heiden MG (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155(2):397–409. https://doi.org/10.1016/j.cell.2013.09.025

    Article  CAS  PubMed  Google Scholar 

  20. Kryczka J, Papiewska-Pajak I, Kowalska MA, Boncela J (2019) Cathepsin B Is Upregulated and Mediates ECM Degradation in Colon Adenocarcinoma HT29 Cells Overexpressing Snail. Cells. https://doi.org/10.3390/cells8030203

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67. https://doi.org/10.1016/j.cell.2010.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, Vander Heiden MG, Miller G, Drebin JA, Bar-Sagi D, Thompson CB, Rabinowitz JD (2015) Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res 75(3):544–553. https://doi.org/10.1158/0008-5472.CAN-14-2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fujimura Y, Ikenaga N, Ohuchida K, Setoyama D, Irie M, Miura D, Wariishi H, Murata M, Mizumoto K, Hashizume M, Tanaka M (2014) Mass spectrometry-based metabolic profiling of gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. Pancreas 43(2):311–318. https://doi.org/10.1097/MPA.0000000000000092

    Article  CAS  PubMed  Google Scholar 

  24. Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Sarkar FH (2011) Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol 8(1):27–33. https://doi.org/10.1038/nrgastro.2010.188

    Article  CAS  PubMed  Google Scholar 

  25. Ohhashi S, Ohuchida K, Mizumoto K, Fujita H, Egami T, Yu J, Toma H, Sadatomi S, Nagai E, Tanaka M (2008) Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer. Anticancer Res 28(4B):2205–2212

    CAS  PubMed  Google Scholar 

  26. Adamska A, Elaskalani O, Emmanouilidi A, Kim M, Abdol Razak NB, Metharom P, Falasca M (2018) Molecular and cellular mechanisms of chemoresistance in pancreatic cancer. Adv Biol Regul 68:77–87. https://doi.org/10.1016/j.jbior.2017.11.007

    Article  CAS  PubMed  Google Scholar 

  27. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T (2006) Cellular pharmacology of gemcitabine. Ann Oncol 17(Suppl 5):v7-12. https://doi.org/10.1093/annonc/mdj941

    Article  PubMed  Google Scholar 

  28. Ritzel MW, Ng AM, Yao SY, Graham K, Loewen SK, Smith KM, Hyde RJ, Karpinski E, Cass CE, Baldwin SA, Young JD (2001) Mol Membr Biol 18(1):65–72. https://doi.org/10.1080/09687680010026313

    Article  CAS  PubMed  Google Scholar 

  29. Hagmann W, Faissner R, Schnolzer M, Lohr M, Jesnowski R (2010) Membrane drug transporters and chemoresistance in human pancreatic carcinoma. Cancers (Basel) 3(1):106–125. https://doi.org/10.3390/cancers3010106

    Article  CAS  Google Scholar 

  30. Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A (2003) Structure of human dCK suggests strategies to improve anticancer and antiviral therapy. Nat Struct Biol 10(7):513–519. https://doi.org/10.1038/nsb942

    Article  CAS  PubMed  Google Scholar 

  31. Li F, Hu G, Jiang Z, Guo J, Wang K, Ouyang K, Wen D, Zhu M, Liang J, Qin X, Zhang L (2012) Identification of NME5 as a contributor to innate resistance to gemcitabine in pancreatic cancer cells. FEBS J 279(7):1261–1273. https://doi.org/10.1111/j.1742-4658.2012.08521.x

    Article  CAS  PubMed  Google Scholar 

  32. Ohmine K, Kawaguchi K, Ohtsuki S, Motoi F, Egawa S, Unno M, Terasaki T (2012) Attenuation of phosphorylation by deoxycytidine kinase is key to acquired gemcitabine resistance in a pancreatic cancer cell line: targeted proteomic and metabolomic analyses in PK9 cells. Pharm Res 29(7):2006–2016. https://doi.org/10.1007/s11095-012-0728-2

    Article  CAS  PubMed  Google Scholar 

  33. Tatarian T, Jiang W, Leiby BE, Grigoli A, Jimbo M, Dabbish N, Neoptolemos JP, Greenhalf W, Costello E, Ghaneh P, Halloran C, Palmer D, Buchler M, Yeo CJ, Winter JM, Brody JR (2018) Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial. Ann Surg 267(2):364–369. https://doi.org/10.1097/SLA.0000000000002088

    Article  PubMed  Google Scholar 

  34. Cohen R, Preta LH, Joste V, Curis E, Huillard O, Jouinot A, Narjoz C, Thomas-Schoemann A, Bellesoeur A, Tiako Meyo M, Quilichini J, Desaulle D, Nicolis I, Cessot A, Vidal M, Goldwasser F, Alexandre J, Blanchet B (2019) Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours. Br J Clin Pharmacol 85(6):1227–1238. https://doi.org/10.1111/bcp.13849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ciccolini J, Serdjebi C, Peters GJ, Giovannetti E (2016) Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother Pharmacol 78(1):1–12. https://doi.org/10.1007/s00280-016-3003-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jordheim LP, Seve P, Tredan O, Dumontet C (2011) The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol 12(7):693–702. https://doi.org/10.1016/S1470-2045(10)70244-8

    Article  CAS  PubMed  Google Scholar 

  37. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527(7579):525–530. https://doi.org/10.1038/nature16064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marcucci F, Stassi G, De Maria R (2016) Epithelial–mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov 15(5):311–325. https://doi.org/10.1038/nrd.2015.13

    Article  CAS  PubMed  Google Scholar 

  39. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139(5):871–890. https://doi.org/10.1016/j.cell.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  40. De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110. https://doi.org/10.1038/nrc3447

    Article  CAS  PubMed  Google Scholar 

  41. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W (2009) Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69(14):5820–5828. https://doi.org/10.1158/0008-5472.CAN-08-2819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tsukasa K, Ding Q, Yoshimitsu M, Miyazaki Y, Matsubara S, Takao S (2015) Slug contributes to gemcitabine resistance through epithelial–mesenchymal transition in CD133(+) pancreatic cancer cells. Hum Cell 28(4):167–174. https://doi.org/10.1007/s13577-015-0117-3

    Article  CAS  PubMed  Google Scholar 

  43. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749. https://doi.org/10.1038/nrc1694

    Article  CAS  PubMed  Google Scholar 

  44. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14(10):611–629. https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323. https://doi.org/10.1016/j.stem.2007.06.002

    Article  CAS  PubMed  Google Scholar 

  46. Zhao J (2016) Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacol Ther 160:145–158. https://doi.org/10.1016/j.pharmthera.2016.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hashimoto O, Shimizu K, Semba S, Chiba S, Ku Y, Yokozaki H, Hori Y (2011) Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1alpha-dependent manner in pancreatic cancer cells. Pathobiology 78(4):181–192. https://doi.org/10.1159/000325538

    Article  CAS  PubMed  Google Scholar 

  48. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284. https://doi.org/10.1038/nrc1590

    Article  CAS  PubMed  Google Scholar 

  49. Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG, Di Fiore PP (2010) Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140(1):62–73. https://doi.org/10.1016/j.cell.2009.12.007

    Article  CAS  PubMed  Google Scholar 

  50. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760. https://doi.org/10.1038/nature05236

    Article  CAS  PubMed  Google Scholar 

  51. Hwang DW, So KS, Kim SC, Park KM, Lee YJ, Kim SW, Choi CM, Rho JK, Choi YJ, Lee JC (2017) Autophagy Induced by CX-4945, a Casein Kinase 2 Inhibitor, Enhances Apoptosis in Pancreatic Cancer Cell Lines. Pancreas 46(4):575–581. https://doi.org/10.1097/MPA.0000000000000780

    Article  CAS  PubMed  Google Scholar 

  52. Yang MC, Wang HC, Hou YC, Tung HL, Chiu TJ, Shan YS (2015) Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer 14:179. https://doi.org/10.1186/s12943-015-0449-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA (2012) The pancreas cancer microenvironment. Clin Cancer Res 18(16):4266–4276. https://doi.org/10.1158/1078-0432.CCR-11-3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Liang C, Shi S, Meng Q, Liang D, Ji S, Zhang B, Qin Y, Xu J, Ni Q, Yu X (2017) Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going. Exp Mol Med 49(12):e406. https://doi.org/10.1038/emm.2017.255

    Article  PubMed  PubMed Central  Google Scholar 

  55. Oettle H (2014) Progress in the knowledge and treatment of advanced pancreatic cancer: from benchside to bedside. Cancer Treat Rev 40(9):1039–1047. https://doi.org/10.1016/j.ctrv.2014.07.003

    Article  PubMed  Google Scholar 

  56. Fu Y, Liu S, Zeng S, Shen H (2018) The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol Cancer 17(1):62. https://doi.org/10.1186/s12943-018-0815-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sunami Y, Haussler J, Kleeff J (2020) Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer. Cancers (Basel). https://doi.org/10.3390/cancers12123770

    Article  Google Scholar 

  58. Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, Kremer D, Hwang RF, Witkiewicz AK, Ying H, Asara JM, Evans RM, Cantley LC, Lyssiotis CA, Kimmelman AC (2016) Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536(7617):479–483. https://doi.org/10.1038/nature19084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chang CI, Liao JC, Kuo L (2001) Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res 61(3):1100–1106

    CAS  PubMed  Google Scholar 

  60. Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275–297. https://doi.org/10.1146/annurev-pathol-011110-130138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513(7519):559–563. https://doi.org/10.1038/nature13490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xiang Y, Miao H (2021) Lipid Metabolism in Tumor-Associated Macrophages. Adv Exp Med Biol 1316:87–101. https://doi.org/10.1007/978-981-33-6785-2_6

    Article  PubMed  Google Scholar 

  63. Amit M, Gil Z (2013) Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase. Oncoimmunology 2(12):e27231. https://doi.org/10.4161/onci.27231

    Article  PubMed  PubMed Central  Google Scholar 

  64. Dangi-Garimella S, Krantz SB, Barron MR, Shields MA, Heiferman MJ, Grippo PJ, Bentrem DJ, Munshi HG (2011) Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2. Cancer Res 71(3):1019–1028. https://doi.org/10.1158/0008-5472.CAN-10-1855

    Article  CAS  PubMed  Google Scholar 

  65. Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, Hamada S, Satoh K, Egawa S, Unno M, Shimosegawa T (2010) Pancreatic stellate cells promote epithelial–mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun 403(3–4):380–384. https://doi.org/10.1016/j.bbrc.2010.11.040

    Article  CAS  PubMed  Google Scholar 

  66. Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E (2009) Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem 284(39):26533–26546. https://doi.org/10.1074/jbc.M109.027466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liberti MV, Locasale JW (2016) The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci 41(3):211–218. https://doi.org/10.1016/j.tibs.2015.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. https://doi.org/10.1126/science.1160809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11(5):325–337. https://doi.org/10.1038/nrc3038

    Article  CAS  PubMed  Google Scholar 

  70. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149(3):656–670. https://doi.org/10.1016/j.cell.2012.01.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Basturk O, Singh R, Kaygusuz E, Balci S, Dursun N, Culhaci N, Adsay NV (2011) GLUT-1 expression in pancreatic neoplasia: implications in pathogenesis, diagnosis, and prognosis. Pancreas 40(2):187–192. https://doi.org/10.1097/MPA.0b013e318201c935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kurahara H, Maemura K, Mataki Y, Sakoda M, Iino S, Kawasaki Y, Arigami T, Mori S, Kijima Y, Ueno S, Shinchi H, Natsugoe S (2018) Significance of glucose transporter Type 1 (GLUT-1) expression in the therapeutic strategy for pancreatic ductal adenocarcinoma. Ann Surg Oncol 25(5):1432–1439. https://doi.org/10.1245/s10434-018-6357-1

    Article  PubMed  Google Scholar 

  73. Gou Q, Dong C, Jin J, Liu Q, Lu W, Shi J, Hou Y (2019) PPARalpha agonist alleviates tumor growth and chemo-resistance associated with the inhibition of glucose metabolic pathway. Eur J Pharmacol 863:172664. https://doi.org/10.1016/j.ejphar.2019.172664

    Article  CAS  PubMed  Google Scholar 

  74. Wang YD, Li SJ, Liao JX (2013) Inhibition of glucose transporter 1 (GLUT1) chemosensitized head and neck cancer cells to cisplatin. Technol Cancer Res Treat 12(6):525–535. https://doi.org/10.7785/tcrt.2012.500343

    Article  CAS  PubMed  Google Scholar 

  75. Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C, Satyamurthy N, Moatamed NA, Huang J, Koepsell H, Barrio JR, Wright EM (2015) Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci USA 112(30):E4111-4119. https://doi.org/10.1073/pnas.1511698112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Varghese E, Samuel SM, Liskova A, Samec M, Kubatka P, Busselberg D (2020) Targeting glucose metabolism to overcome resistance to anticancer chemotherapy in breast cancer. Cancers (Basel). https://doi.org/10.3390/cancers12082252

    Article  Google Scholar 

  77. Ahn KJ, Hwang HS, Park JH, Bang SH, Kang WJ, Yun M, Lee JD (2009) Evaluation of the role of hexokinase type II in cellular proliferation and apoptosis using human hepatocellular carcinoma cell lines. J Nucl Med 50(9):1525–1532. https://doi.org/10.2967/jnumed.108.060780

    Article  CAS  PubMed  Google Scholar 

  78. Fan K, Fan Z, Cheng H, Huang Q, Yang C, Jin K, Luo G, Yu X, Liu C (2019) Hexokinase 2 dimerization and interaction with voltage-dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer. Cancer Med 8(13):5903–5915. https://doi.org/10.1002/cam4.2463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684. https://doi.org/10.1038/nrd3504

    Article  CAS  PubMed  Google Scholar 

  80. Sato-Tadano A, Suzuki T, Amari M, Takagi K, Miki Y, Tamaki K, Watanabe M, Ishida T, Sasano H, Ohuchi N (2013) Hexokinase II in breast carcinoma: a potent prognostic factor associated with hypoxia-inducible factor-1alpha and Ki-67. Cancer Sci 104(10):1380–1388. https://doi.org/10.1111/cas.12238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dai S, Peng Y, Zhu Y, Xu D, Zhu F, Xu W, Chen Q, Zhu X, Liu T, Hou C, Wu J, Miao Y (2020) Glycolysis promotes the progression of pancreatic cancer and reduces cancer cell sensitivity to gemcitabine. Biomed Pharmacother 121:109521. https://doi.org/10.1016/j.biopha.2019.109521

    Article  CAS  PubMed  Google Scholar 

  82. Zhao H, Duan Q, Zhang Z, Li H, Wu H, Shen Q, Wang C, Yin T (2017) Up-regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine-resistant pancreatic cancer cells. J Cell Mol Med 21(9):2055–2067. https://doi.org/10.1111/jcmm.13126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nakano A, Tsuji D, Miki H, Cui Q, El Sayed SM, Ikegame A, Oda A, Amou H, Nakamura S, Harada T, Fujii S, Kagawa K, Takeuchi K, Sakai A, Ozaki S, Okano K, Nakamura T, Itoh K, Matsumoto T, Abe M (2011) Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells. PLoS ONE 6(11):e27222. https://doi.org/10.1371/journal.pone.0027222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, Gao G, Zhang A, Xia X, Brasher H, Widger W, Ellis LM, Weihua Z (2012) Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res 72(1):304–314. https://doi.org/10.1158/0008-5472.CAN-11-1674

    Article  CAS  PubMed  Google Scholar 

  85. Chapiro J, Sur S, Savic LJ, Ganapathy-Kanniappan S, Reyes J, Duran R, Thiruganasambandam SC, Moats CR, Lin M, Luo W, Tran PT, Herman JM, Semenza GL, Ewald AJ, Vogelstein B, Geschwind JF (2014) Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. Clin Cancer Res 20(24):6406–6417. https://doi.org/10.1158/1078-0432.CCR-14-1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Xiao H, Li S, Zhang D, Liu T, Yu M, Wang F (2013) Separate and concurrent use of 2-deoxy-D-glucose and 3-bromopyruvate in pancreatic cancer cells. Oncol Rep 29(1):329–334. https://doi.org/10.3892/or.2012.2085

    Article  CAS  PubMed  Google Scholar 

  87. Clem BF, O’Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA 2nd, Klarer AC, Redman R, Miller DM, Trent JO, Telang S, Chesney J (2013) Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther 12(8):1461–1470. https://doi.org/10.1158/1535-7163.MCT-13-0097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kotiah SD, Caro J (2010) Elevation of PFKFB3 and TIGAR levels in pancreatic cancer. J Clin Oncol 28(15_suppl):e14679–e14679. https://doi.org/10.1200/jco.2010.28.15_suppl.e14679

    Article  Google Scholar 

  89. Richardson DA, Sritangos P, James AD, Sultan A, Bruce JIE (2020) Metabolic regulation of calcium pumps in pancreatic cancer: role of phosphofructokinase-fructose-bisphosphatase-3 (PFKFB3). Cancer Metab 8:2. https://doi.org/10.1186/s40170-020-0210-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ozcan SC, Sarioglu A, Altunok TH, Akkoc A, Guzel S, Guler S, Imbert-Fernandez Y, Muchut RJ, Iglesias AA, Gurpinar Y, Clem AL, Chesney JA, Yalcin A (2020) PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells. Mol Cell Biochem 470(1–2):115–129. https://doi.org/10.1007/s11010-020-03751-5

    Article  CAS  PubMed  Google Scholar 

  91. He Y, Luo Y, Zhang D, Wang X, Zhang P, Li H, Ejaz S, Liang S (2019) PGK1-mediated cancer progression and drug resistance. Am J Cancer Res 9(11):2280–2302

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Daly EB, Wind T, Jiang XM, Sun L, Hogg PJ (2004) Secretion of phosphoglycerate kinase from tumour cells is controlled by oxygen-sensing hydroxylases. Biochim Biophys Acta 1691(1):17–22. https://doi.org/10.1016/j.bbamcr.2003.11.004

    Article  CAS  PubMed  Google Scholar 

  93. Ariosa AR, Klionsky DJ (2017) A novel role for a glycolytic pathway kinase in regulating autophagy has implications in cancer therapy. Autophagy 13(7):1091–1092. https://doi.org/10.1080/15548627.2017.1321723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhou JW, Tang JJ, Sun W, Wang H (2019) PGK1 facilities cisplatin chemoresistance by triggering HSP90/ERK pathway mediated DNA repair and methylation in endometrial endometrioid adenocarcinoma. Mol Med 25(1):11. https://doi.org/10.1186/s10020-019-0079-0

    Article  PubMed  PubMed Central  Google Scholar 

  95. Huang Z, Zhou L, Chen Z, Nice EC, Huang C (2016) Stress management by autophagy: implications for chemoresistance. Int J Cancer 139(1):23–32. https://doi.org/10.1002/ijc.29990

    Article  CAS  PubMed  Google Scholar 

  96. Sun R, Meng X, Pu Y, Sun F, Man Z, Zhang J, Yin L, Pu Y (2019) Overexpression of HIF-1a could partially protect K562 cells from 1,4-benzoquinone induced toxicity by inhibiting ROS, apoptosis and enhancing glycolysis. Toxicol In Vitro 55:18–23. https://doi.org/10.1016/j.tiv.2018.11.005

    Article  CAS  PubMed  Google Scholar 

  97. Schneider CC, Archid R, Fischer N, Buhler S, Venturelli S, Berger A, Burkard M, Kirschniak A, Bachmann R, Konigsrainer A, Glatzle J, Zieker D (2015) Metabolic alteration–overcoming therapy resistance in gastric cancer via PGK-1 inhibition in a combined therapy with standard chemotherapeutics. Int J Surg 22:92–98. https://doi.org/10.1016/j.ijsu.2015.08.020

    Article  PubMed  Google Scholar 

  98. Liang C, Shi S, Qin Y, Meng Q, Hua J, Hu Q, Ji S, Zhang B, Xu J, Yu X (2020) Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer. Gut 69(5):888–900. https://doi.org/10.1136/gutjnl-2018-317163

    Article  CAS  PubMed  Google Scholar 

  99. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452(7184):230–233. https://doi.org/10.1038/nature06734

    Article  CAS  PubMed  Google Scholar 

  100. Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, Simmet T, Seufferlein T (2016) PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. Mol Cancer 15:3. https://doi.org/10.1186/s12943-015-0490-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tamada M, Suematsu M, Saya H (2012) Pyruvate kinase M2: multiple faces for conferring benefits on cancer cells. Clin Cancer Res 18(20):5554–5561. https://doi.org/10.1158/1078-0432.CCR-12-0859

    Article  CAS  PubMed  Google Scholar 

  102. Icard P, Fournel L, Wu Z, Alifano M, Lincet H (2019) Interconnection between metabolism and cell cycle in cancer. Trends Biochem Sci 44(6):490–501. https://doi.org/10.1016/j.tibs.2018.12.007

    Article  CAS  PubMed  Google Scholar 

  103. Kim DJ, Park YS, Kang MG, You YM, Jung Y, Koo H, Kim JA, Kim MJ, Hong SM, Lee KB, Jang JJ, Park KC, Yeom YI (2015) Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells. Exp Cell Res 336(1):119–129. https://doi.org/10.1016/j.yexcr.2015.05.017

    Article  CAS  PubMed  Google Scholar 

  104. James AD, Richardson DA, Oh IW, Sritangos P, Attard T, Barrett L, Bruce JIE (2020) Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2). Br J Cancer 122(2):266–278. https://doi.org/10.1038/s41416-019-0675-3

    Article  CAS  PubMed  Google Scholar 

  105. Su Q, Tao T, Tang L, Deng J, Darko KO, Zhou S, Peng M, He S, Zeng Q, Chen AF, Yang X (2018) Down-regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer. J Cell Mol Med 22(5):2774–2790. https://doi.org/10.1111/jcmm.13571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang X, Zhang F, Wu XR (2017) Inhibition of pyruvate kinase M2 markedly reduces chemoresistance of advanced bladder cancer to cisplatin. Sci Rep 7:45983. https://doi.org/10.1038/srep45983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tian S, Li P, Sheng S, Jin X (2018) Upregulation of pyruvate kinase M2 expression by fatty acid synthase contributes to gemcitabine resistance in pancreatic cancer. Oncol Lett 15(2):2211–2217. https://doi.org/10.3892/ol.2017.7598

    Article  CAS  PubMed  Google Scholar 

  108. Yu L, Teoh ST, Ensink E, Ogrodzinski MP, Yang C, Vazquez AI, Lunt SY (2019) Cysteine catabolism and the serine biosynthesis pathway support pyruvate production during pyruvate kinase knockdown in pancreatic cancer cells. Cancer Metab 7:13. https://doi.org/10.1186/s40170-019-0205-z

    Article  PubMed  PubMed Central  Google Scholar 

  109. Mohammad GH, Olde Damink SW, Malago M, Dhar DK, Pereira SP (2016) Pyruvate kinase M2 and lactate dehydrogenase A are overexpressed in pancreatic cancer and correlate with poor outcome. PLoS ONE 11(3):e0151635. https://doi.org/10.1371/journal.pone.0151635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yu Y, Deck JA, Hunsaker LA, Deck LM, Royer RE, Goldberg E, Vander Jagt DL (2001) Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4. Biochem Pharmacol 62(1):81–89. https://doi.org/10.1016/s0006-2952(01)00636-0

    Article  CAS  PubMed  Google Scholar 

  111. Li S, Gao J, Zhuang X, Zhao C, Hou X, Xing X, Chen C, Liu Q, Liu S, Luo Y (2019) Cyclin G2 inhibits the warburg effect and tumour progression by suppressing LDHA phosphorylation in glioma. Int J Biol Sci 15(3):544–555. https://doi.org/10.7150/ijbs.30297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mohammad GH, Vassileva V, Acedo P, Olde Damink SWM, Malago M, Dhar DK, Pereira SP (2019) Targeting pyruvate kinase M2 and lactate dehydrogenase A is an effective combination strategy for the treatment of pancreatic cancer. Cancers (Basel). https://doi.org/10.3390/cancers11091372

    Article  Google Scholar 

  113. Liu Z, Zhou M, Zhao Y, Yan D, Liu H, Tan M (2011) Overcoming chemotherapy resistance by targeting LDHA mediated glycolysis. Cancer Res. https://doi.org/10.1158/1538-7445.Am2011-2130

    Article  PubMed  PubMed Central  Google Scholar 

  114. Maftouh M, Avan A, Sciarrillo R, Granchi C, Leon LG, Rani R, Funel N, Smid K, Honeywell R, Boggi U, Minutolo F, Peters GJ, Giovannetti E (2014) Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br J Cancer 110(1):172–182. https://doi.org/10.1038/bjc.2013.681

    Article  CAS  PubMed  Google Scholar 

  115. Giovannetti E, Leon LG, Gomez VE, Zucali PA, Minutolo F, Peters GJ (2016) A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells, and modulated the expression of the human equilibrative transporter-1. Nucleosides Nucleotides Nucleic Acids 35(10–12):643–651. https://doi.org/10.1080/15257770.2016.1149193

    Article  CAS  PubMed  Google Scholar 

  116. Doherty JR, Cleveland JL (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123(9):3685–3692. https://doi.org/10.1172/JCI69741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. McDonald PC, Chafe SC, Dedhar S (2016) Overcoming hypoxia-mediated tumor progression: combinatorial approaches targeting pH regulation, angiogenesis and immune dysfunction. Front Cell Dev Biol 4:27. https://doi.org/10.3389/fcell.2016.00027

    Article  PubMed  PubMed Central  Google Scholar 

  118. Puri S, Juvale K (2020) Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure–activity relationship insights. Eur J Med Chem 199:112393. https://doi.org/10.1016/j.ejmech.2020.112393

    Article  CAS  PubMed  Google Scholar 

  119. Kong SC, Nohr-Nielsen A, Zeeberg K, Reshkin SJ, Hoffmann EK, Novak I, Pedersen SF (2016) Monocarboxylate Transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells. Pancreas 45(7):1036–1047. https://doi.org/10.1097/MPA.0000000000000571

    Article  CAS  PubMed  Google Scholar 

  120. Le Floch R, Chiche J, Marchiq I, Naiken T, Ilc K, Murray CM, Critchlow SE, Roux D, Simon MP, Pouyssegur J (2011) CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci USA 108(40):16663–16668. https://doi.org/10.1073/pnas.1106123108

    Article  PubMed  PubMed Central  Google Scholar 

  121. Afonso J, Santos LL, Miranda-Goncalves V, Morais A, Amaro T, Longatto-Filho A, Baltazar F (2015) CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance. Mol Carcinog 54(11):1451–1466. https://doi.org/10.1002/mc.22222

    Article  CAS  PubMed  Google Scholar 

  122. Kuang Y, Wang S, Tang L, Hai J, Yan G, Liao L (2018) Cluster of differentiation 147 mediates chemoresistance in breast cancer by affecting vacuolar H(+)-ATPase expression and activity. Oncol Lett 15(5):7279–7290. https://doi.org/10.3892/ol.2018.8199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhou S, Liao L, Chen C, Zeng W, Liu S, Su J, Zhao S, Chen M, Kuang Y, Chen X, Li J (2013) CD147 mediates chemoresistance in breast cancer via ABCG2 by affecting its cellular localization and dimerization. Cancer Lett 337(2):285–292. https://doi.org/10.1016/j.canlet.2013.04.025

    Article  CAS  PubMed  Google Scholar 

  124. Schneiderhan W, Scheler M, Holzmann KH, Marx M, Gschwend JE, Bucholz M, Gress TM, Seufferlein T, Adler G, Oswald F (2009) CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut 58(10):1391–1398. https://doi.org/10.1136/gut.2009.181412

    Article  CAS  PubMed  Google Scholar 

  125. Kuang YH, Chen X, Su J, Wu LS, Liao LQ, Li D, Chen ZS, Kanekura T (2009) RNA interference targeting the CD147 induces apoptosis of multi-drug resistant cancer cells related to XIAP depletion. Cancer Lett 276(2):189–195. https://doi.org/10.1016/j.canlet.2008.11.010

    Article  CAS  PubMed  Google Scholar 

  126. Kang MJ, Kim HP, Lee KS, Yoo YD, Kwon YT, Kim KM, Kim TY, Yi EC (2013) Proteomic analysis reveals that CD147/EMMPRIN confers chemoresistance in cancer stem cell-like cells. Proteomics 13(10–11):1714–1725. https://doi.org/10.1002/pmic.201200511

    Article  CAS  PubMed  Google Scholar 

  127. Zhou Y, Zheng M, Liu Z, Yang H, Zhu P, Jiang JL, Tang J, Chen ZN (2020) CD147 promotes DNA damage response and gemcitabine resistance via targeting ATM/ATR/p53 and affects prognosis in pancreatic cancer. Biochem Biophys Res Commun 528(1):62–70. https://doi.org/10.1016/j.bbrc.2020.05.005

    Article  CAS  PubMed  Google Scholar 

  128. Patra KC, Hay N (2014) The pentose phosphate pathway and cancer. Trends Biochem Sci 39(8):347–354. https://doi.org/10.1016/j.tibs.2014.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Al Hanjori AS, Alshaer W, Anati B, Wehaibi S, Zihlif M (2020) Studying Antitumor effects of sirna gene silencing of some metabolic genes in pancreatic ductal adenocarcinoma. Curr Mol Pharmacol. https://doi.org/10.2174/1874467213666201012162250

    Article  Google Scholar 

  130. Chen H, Wu D, Bao L, Yin T, Lei D, Yu J, Tong X (2019) 6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming. Biomed Pharmacother 111:1353–1358. https://doi.org/10.1016/j.biopha.2019.01.028

    Article  CAS  PubMed  Google Scholar 

  131. Li Q, Qin T, Bi Z, Hong H, Ding L, Chen J, Wu W, Lin X, Fu W, Zheng F, Yao Y, Luo ML, Saw PE, Wulf GM, Xu X, Song E, Yao H, Hu H (2020) Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer. Nat Commun 11(1):1456. https://doi.org/10.1038/s41467-020-15308-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lin R, Elf S, Shan C, Kang HB, Ji Q, Zhou L, Hitosugi T, Zhang L, Zhang S, Seo JH, Xie J, Tucker M, Gu TL, Sudderth J, Jiang L, Mitsche M, DeBerardinis RJ, Wu S, Li Y, Mao H, Chen PR, Wang D, Chen GZ, Hurwitz SJ, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Lei Q, Brat DJ, Ye K, Boggon TJ, He C, Kang S, Fan J, Chen J (2015) 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol 17(11):1484–1496. https://doi.org/10.1038/ncb3255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Giacomini I, Ragazzi E, Pasut G, Montopoli M (2020) The Pentose Phosphate Pathway and Its Involvement in Cisplatin Resistance. Int J Mol Sci. https://doi.org/10.3390/ijms21030937

    Article  PubMed  PubMed Central  Google Scholar 

  134. Preuss J, Richardson AD, Pinkerton A, Hedrick M, Sergienko E, Rahlfs S, Becker K, Bode L (2013) Identification and characterization of novel human glucose-6-phosphate dehydrogenase inhibitors. J Biomol Screen 18(3):286–297. https://doi.org/10.1177/1087057112462131

    Article  CAS  PubMed  Google Scholar 

  135. Sharma N, Bhushan A, He J, Kaushal G, Bhardwaj V (2020) Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase. Cancer Metab 8:19. https://doi.org/10.1186/s40170-020-00226-5

    Article  PubMed  PubMed Central  Google Scholar 

  136. Yin X, Tang B, Li JH, Wang Y, Zhang L, Xie XY, Zhang BH, Qiu SJ, Wu WZ, Ren ZG (2017) ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway. J Exp Clin Cancer Res 36(1):166. https://doi.org/10.1186/s13046-017-0637-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yang X, Peng X, Huang J (2018) Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation. Clin Transl Oncol 20(9):1145–1152. https://doi.org/10.1007/s12094-018-1833-4

    Article  CAS  PubMed  Google Scholar 

  138. Bechard ME, Word AE, Tran AV, Liu X, Locasale JW, McDonald OG (2018) Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases. Oncogene 37(38):5248–5256. https://doi.org/10.1038/s41388-018-0346-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Riganti C, Gazzano E, Polimeni M, Aldieri E, Ghigo D (2012) The pentose phosphate pathway: an antioxidant defense and a crossroad in tumor cell fate. Free Radic Biol Med 53(3):421–436. https://doi.org/10.1016/j.freeradbiomed.2012.05.006

    Article  CAS  PubMed  Google Scholar 

  140. Friesen C, Kiess Y, Debatin KM (2004) A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death Differ 11(Suppl 1):S73-85. https://doi.org/10.1038/sj.cdd.4401431

    Article  CAS  PubMed  Google Scholar 

  141. Recktenwald CV, Kellner R, Lichtenfels R, Seliger B (2008) Altered detoxification status and increased resistance to oxidative stress by K-ras transformation. Cancer Res 68(24):10086–10093. https://doi.org/10.1158/0008-5472.CAN-08-0360

    Article  CAS  PubMed  Google Scholar 

  142. Galadari S, Rahman A, Pallichankandy S, Thayyullathil F (2017) Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med 104:144–164. https://doi.org/10.1016/j.freeradbiomed.2017.01.004

    Article  CAS  PubMed  Google Scholar 

  143. Akella NM, Ciraku L, Reginato MJ (2019) Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer. BMC Biol 17(1):52. https://doi.org/10.1186/s12915-019-0671-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95. https://doi.org/10.1038/nrc2981

    Article  CAS  PubMed  Google Scholar 

  145. Liu Y, Cao Y, Pan X, Shi M, Wu Q, Huang T, Jiang H, Li W, Zhang J (2018) O-GlcNAc elevation through activation of the hexosamine biosynthetic pathway enhances cancer cell chemoresistance. Cell Death Dis 9(5):485. https://doi.org/10.1038/s41419-018-0522-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ma Z, Vocadlo DJ, Vosseller K (2013) Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-kappaB activity in pancreatic cancer cells. J Biol Chem 288(21):15121–15130. https://doi.org/10.1074/jbc.M113.470047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chen W, Do KC, Saxton B, Leng S, Filipczak P, Tessema M, Belinsky SA, Lin Y (2019) Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small-cell lung cancer cells. Mol Carcinog 58(6):1046–1055. https://doi.org/10.1002/mc.22992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Luanpitpong S, Angsutararux P, Samart P, Chanthra N, Chanvorachote P, Issaragrisil S (2017) Hyper-O-GlcNAcylation induces cisplatin resistance via regulation of p53 and c-Myc in human lung carcinoma. Sci Rep 7(1):10607. https://doi.org/10.1038/s41598-017-10886-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Guerra F, Arbini AA, Moro L (2017) Mitochondria and cancer chemoresistance. Biochim Biophys Acta Bioenerg 1858(8):686–699. https://doi.org/10.1016/j.bbabio.2017.01.012

    Article  CAS  PubMed  Google Scholar 

  150. Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and cancer. Cell 166(3):555–566. https://doi.org/10.1016/j.cell.2016.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Falasca M, Kim M, Casari I (2016) Pancreatic cancer: current research and future directions. Biochim Biophys Acta 1865(2):123–132. https://doi.org/10.1016/j.bbcan.2016.01.001

    Article  CAS  PubMed  Google Scholar 

  152. Valle S, Alcala S, Martin-Hijano L, Cabezas-Sainz P, Navarro D, Munoz ER, Yuste L, Tiwary K, Walter K, Ruiz-Canas L, Alonso-Nocelo M, Rubiolo JA, Gonzalez-Arnay E, Heeschen C, Garcia-Bermejo L, Hermann PC, Sanchez L, Sancho P, Fernandez-Moreno MA, Sainz B Jr (2020) Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells. Nat Commun 11(1):5265. https://doi.org/10.1038/s41467-020-18954-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, Draetta GF (2014) Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514(7524):628–632. https://doi.org/10.1038/nature13611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rademaker G, Hennequiere V, Brohee L, Nokin MJ, Lovinfosse P, Durieux F, Gofflot S, Bellier J, Costanza B, Herfs M, Peiffer R, Bettendorff L, Deroanne C, Thiry M, Delvenne P, Hustinx R, Bellahcene A, Castronovo V, Peulen O (2018) Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene 37(32):4398–4412. https://doi.org/10.1038/s41388-018-0287-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Wang Z, Dong C (2019) Gluconeogenesis in cancer: function and regulation of PEPCK, FBPase, and G6Pase. Trends Cancer 5(1):30–45. https://doi.org/10.1016/j.trecan.2018.11.003

    Article  CAS  PubMed  Google Scholar 

  156. Jin X, Pan Y, Wang L, Ma T, Zhang L, Tang AH, Billadeau DD, Wu H, Huang H (2017) Fructose-1,6-bisphosphatase Inhibits ERK activation and bypasses gemcitabine resistance in pancreatic cancer by blocking IQGAP1-MAPK interaction. Cancer Res 77(16):4328–4341. https://doi.org/10.1158/0008-5472.CAN-16-3143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Yang C, Zhu S, Yang H, Fan P, Meng Z, Zhao J, Zhang K, Jin X (2020) FBP1 binds to the bromodomain of BRD4 to inhibit pancreatic cancer progression. Am J Cancer Res 10(2):523–535

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD, Mathew LK, Mancuso A, Gade TP, Keith B, Nissim I, Simon MC (2014) Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513(7517):251–255. https://doi.org/10.1038/nature13557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lieu EL, Nguyen T, Rhyne S, Kim J (2020) Amino acids in cancer. Exp Mol Med 52(1):15–30. https://doi.org/10.1038/s12276-020-0375-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Coothankandaswamy V, Cao S, Xu Y, Prasad PD, Singh PK, Reynolds CP, Yang S, Ogura J, Ganapathy V, Bhutia YD (2016) Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer. Br J Pharmacol 173(23):3292–3306. https://doi.org/10.1111/bph.13616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Cui H, Darmanin S, Natsuisaka M, Kondo T, Asaka M, Shindoh M, Higashino F, Hamuro J, Okada F, Kobayashi M, Nakagawa K, Koide H, Kobayashi M (2007) Enhanced expression of asparagine synthetase under glucose-deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and cisplatin. Cancer Res 67(7):3345–3355. https://doi.org/10.1158/0008-5472.CAN-06-2519

    Article  CAS  PubMed  Google Scholar 

  162. Biancur D, Kimmelman A (2018) The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. Biochim Biophys Acta Rev Cancer 1870(1):67–75. https://doi.org/10.1016/j.bbcan.2018.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Grabocka E, Nofal M, Drebin JA, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, Bar-Sagi D (2013) Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497(7451):633–637. https://doi.org/10.1038/nature12138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496(7443):101–105. https://doi.org/10.1038/nature12040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chen R, Lai LA, Sullivan Y, Wong M, Wang L, Riddell J, Jung L, Pillarisetty VG, Brentnall TA, Pan S (2017) Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer. Sci Rep 7(1):7950. https://doi.org/10.1038/s41598-017-08436-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Sivanand S, Vander Heiden MG (2020) Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell 37(2):147–156. https://doi.org/10.1016/j.ccell.2019.12.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Katagiri R, Goto A, Nakagawa T, Nishiumi S, Kobayashi T, Hidaka A, Budhathoki S, Yamaji T, Sawada N, Shimazu T, Inoue M, Iwasaki M, Yoshida M, Tsugane S (2018) Increased levels of branched-chain amino acid associated with increased risk of pancreatic cancer in a prospective case-control study of a large cohort. Gastroenterology 155(5):1474-1482 e1471. https://doi.org/10.1053/j.gastro.2018.07.033

    Article  CAS  PubMed  Google Scholar 

  168. Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, Yuan C, Bao Y, Townsend MK, Tworoger SS, Davidson SM, Papagiannakopoulos T, Yang A, Dayton TL, Ogino S, Stampfer MJ, Giovannucci EL, Qian ZR, Rubinson DA, Ma J, Sesso HD, Gaziano JM, Cochrane BB, Liu S, Wactawski-Wende J, Manson JE, Pollak MN, Kimmelman AC, Souza A, Pierce K, Wang TJ, Gerszten RE, Fuchs CS, Vander Heiden MG, Wolpin BM (2014) Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20(10):1193–1198. https://doi.org/10.1038/nm.3686s

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Krall AS, Xu S, Graeber TG, Braas D, Christofk HR (2016) Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat Commun 7:11457. https://doi.org/10.1038/ncomms11457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Gwinn DM, Lee AG, Briones-Martin-Del-Campo M, Conn CS, Simpson DR, Scott AI, Le A, Cowan TM, Ruggero D, Sweet-Cordero EA (2018) Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to l-asparaginase. Cancer Cell 33(1):91-107 e106. https://doi.org/10.1016/j.ccell.2017.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Yu Q, Wang X, Wang L, Zheng J, Wang J, Wang B (2016) Knockdown of asparagine synthetase (ASNS) suppresses cell proliferation and inhibits tumor growth in gastric cancer cells. Scand J Gastroenterol 51(10):1220–1226. https://doi.org/10.1080/00365521.2016.1190399

    Article  CAS  PubMed  Google Scholar 

  172. Panosyan EH, Wang Y, Xia P, Lee WN, Pak Y, Laks DR, Lin HJ, Moore TB, Cloughesy TF, Kornblum HI, Lasky JL 3rd (2014) Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors. Mol Cancer Res 12(5):694–702. https://doi.org/10.1158/1541-7786.MCR-13-0576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Tang L, Zeng J, Geng P, Fang C, Wang Y, Sun M, Wang C, Wang J, Yin P, Hu C, Guo L, Yu J, Gao P, Li E, Zhuang Z, Xu G, Liu Y (2018) Global metabolic profiling identifies a pivotal role of proline and hydroxyproline metabolism in supporting hypoxic response in hepatocellular carcinoma. Clin Cancer Res 24(2):474–485. https://doi.org/10.1158/1078-0432.CCR-17-1707

    Article  CAS  PubMed  Google Scholar 

  174. Olivares O, Mayers JR, Gouirand V, Torrence ME, Gicquel T, Borge L, Lac S, Roques J, Lavaut MN, Berthezene P, Rubis M, Secq V, Garcia S, Moutardier V, Lombardo D, Iovanna JL, Tomasini R, Guillaumond F, Vander Heiden MG, Vasseur S (2017) Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun 8:16031. https://doi.org/10.1038/ncomms16031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogenesis 5:e189. https://doi.org/10.1038/oncsis.2015.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Petan T, Jarc E, Jusovic M (2018) Lipid droplets in cancer: guardians of fat in a stressful world. Mol. https://doi.org/10.3390/molecules23081941

    Article  Google Scholar 

  177. Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, Bobrovnikova-Marjon E, Diehl JA, Keith B, Simon MC (2015) HIF2alpha-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov 5(6):652–667. https://doi.org/10.1158/2159-8290.CD-14-1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Cotte AK, Aires V, Fredon M, Limagne E, Derangere V, Thibaudin M, Humblin E, Scagliarini A, de Barros JP, Hillon P, Ghiringhelli F, Delmas D (2018) Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nat Commun 9(1):322. https://doi.org/10.1038/s41467-017-02732-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, Lac S, Borge L, Roques J, Gayet O, Pinault M, Guimaraes C, Nigri J, Loncle C, Lavaut MN, Garcia S, Tailleux A, Staels B, Calvo E, Tomasini R, Iovanna JL, Vasseur S (2015) Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci USA 112(8):2473–2478. https://doi.org/10.1073/pnas.1421601112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Swierczynski J, Hebanowska A, Sledzinski T (2014) Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. World J Gastroenterol 20(9):2279–2303. https://doi.org/10.3748/wjg.v20.i9.2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Edmunds LR, Sharma L, Kang A, Lu J, Vockley J, Basu S, Uppala R, Goetzman ES, Beck ME, Scott D, Prochownik EV (2014) c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate. J Biol Chem 289(36):25382–25392. https://doi.org/10.1074/jbc.M114.580662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Alo PL, Amini M, Piro F, Pizzuti L, Sebastiani V, Botti C, Murari R, Zotti G, Di Tondo U (2007) Immunohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma. Anticancer Res 27(4B):2523–2527

    CAS  PubMed  Google Scholar 

  183. Tadros S, Shukla SK, King RJ, Gunda V, Vernucci E, Abrego J, Chaika NV, Yu F, Lazenby AJ, Berim L, Grem J, Sasson AR, Singh PK (2017) De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer. Cancer Res 77(20):5503–5517. https://doi.org/10.1158/0008-5472.CAN-16-3062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Bauerschlag DO, Maass N, Leonhardt P, Verburg FA, Pecks U, Zeppernick F, Morgenroth A, Mottaghy FM, Tolba R, Meinhold-Heerlein I, Brautigam K (2015) Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer. J Transl Med 13:146. https://doi.org/10.1186/s12967-015-0511-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sun Y, He W, Luo M, Zhou Y, Chang G, Ren W, Wu K, Li X, Shen J, Zhao X, Hu Y (2015) SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism. Tumour Biol 36(6):4133–4141. https://doi.org/10.1007/s13277-015-3047-5

    Article  CAS  PubMed  Google Scholar 

  186. Wang X, Xie J, Lu X, Li H, Wen C, Huo Z, Xie J, Shi M, Tang X, Chen H, Peng C, Fang Y, Deng X, Shen B (2017) Melittin inhibits tumor growth and decreases resistance to gemcitabine by downregulating cholesterol pathway gene CLU in pancreatic ductal adenocarcinoma. Cancer Lett 399:1–9. https://doi.org/10.1016/j.canlet.2017.04.012

    Article  CAS  PubMed  Google Scholar 

  187. Li J, Gu D, Lee SS, Song B, Bandyopadhyay S, Chen S, Konieczny SF, Ratliff TL, Liu X, Xie J, Cheng JX (2016) Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 35(50):6378–6388. https://doi.org/10.1038/onc.2016.168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Li J, Qu X, Tian J, Zhang JT, Cheng JX (2018) Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation. PLoS ONE 13(2):e0193318. https://doi.org/10.1371/journal.pone.0193318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Jin H, He Y, Zhao P, Hu Y, Tao J, Chen J, Huang Y (2019) Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery. Theranostics 9(1):265–278. https://doi.org/10.7150/thno.27246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Yang J, Zaman MM, Vlasakov I, Roy R, Huang L, Martin CR, Freedman SD, Serhan CN, Moses MA (2019) Adipocytes promote ovarian cancer chemoresistance. Sci Rep 9(1):13316. https://doi.org/10.1038/s41598-019-49649-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, Somlo G, Jandial R, Ann D, Hanash S, Jove R, Yu H (2018) JAK/STAT3-Regulated Fatty Acid beta-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab 27(1):136-150 e135. https://doi.org/10.1016/j.cmet.2017.11.001

    Article  CAS  PubMed  Google Scholar 

  192. Carracedo A, Cantley LC, Pandolfi PP (2013) Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13(4):227–232. https://doi.org/10.1038/nrc3483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Shin SC, Thomas D, Radhakrishnan P, Hollingsworth MA (2020) Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2020.02.018

    Article  PubMed  PubMed Central  Google Scholar 

  194. Meyer KA, Neeley CK, Baker NA, Washabaugh AR, Flesher CG, Nelson BS, Frankel TL, Lumeng CN, Lyssiotis CA, Wynn ML, Rhim AD, O’Rourke RW (2016) Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer. Biochem Biophys Rep 7:144–149. https://doi.org/10.1016/j.bbrep.2016.06.004

    Article  PubMed  PubMed Central  Google Scholar 

  195. Bronte V, Tortora G (2016) Adipocytes and neutrophils give a helping hand to pancreatic cancers. Cancer Discov 6(8):821–823. https://doi.org/10.1158/2159-8290.CD-16-0682

    Article  CAS  PubMed  Google Scholar 

  196. Liang C, Qin Y, Zhang B, Ji S, Shi S, Xu W, Liu J, Xiang J, Liang D, Hu Q, Liu L, Liu C, Luo G, Ni Q, Xu J, Yu X (2016) Energy sources identify metabolic phenotypes in pancreatic cancer. Acta Biochim Biophys Sin (Shanghai) 48(11):969–979. https://doi.org/10.1093/abbs/gmw097

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the editors of AJE (American Journal Experts) for their help in editing the manuscript. This study was supported by the National Natural Science Foundation of China (No. 81902428, 81802352 and 81772555), the Shanghai Sailing Program (No. 19YF1409400), the National Science Foundation for Distinguished Young Scholars of China (No. 81625016), Clinical and Scientific Innovation Project of Shanghai Hospital Development Center (SHDC12018109) and Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057).

Funding

This study was supported by the National Natural Science Foundation of China (No. 81902428, 81802352 and 81772555), the Shanghai Sailing Program (No. 19YF1409400), the National Science Foundation for Distinguished Young Scholars of China (No. 81625016), Clinical and Scientific Innovation Project of Shanghai Hospital Development Center (SHDC12018109) and Scientific Innovation Project of Shanghai Education Committee (2019–01-07–00-07-E00057).

Author information

Author notes

  1. Abudureyimu Tuerhong, Jin Xu and Si Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong’An Road, Shanghai, 200032, People’s Republic of China

    Abudureyimu Tuerhong, Jin Xu, Si Shi, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu & Chen Liang

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China

    Abudureyimu Tuerhong, Jin Xu, Si Shi, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu & Chen Liang

  3. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People’s Republic of China

    Abudureyimu Tuerhong, Jin Xu, Si Shi, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu & Chen Liang

  4. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People’s Republic of China

    Abudureyimu Tuerhong, Jin Xu, Si Shi, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu & Chen Liang

Authors
  1. Abudureyimu Tuerhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Si Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qingcai Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xianjun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chen Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CL, WW and XJY conceived the review, and AT, SS and JX undertook the initial research and writing. ZT, QCM, JH, JL, BZ, and WW were involved in writing, reviewing and graphing, and all authors contributed to the final version.

Corresponding authors

Correspondence to Xianjun Yu or Chen Liang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Consent for publication

All authors consent to publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tuerhong, A., Xu, J., Shi, S. et al. Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma. Cell. Mol. Life Sci. 78, 5505–5526 (2021). https://doi.org/10.1007/s00018-021-03866-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-021-03866-y

Keywords

Search

Navigation