Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis
<p>Auraptene exerts anti-tumor effects in HCC cells. (<b>A</b>) The molecular formula of auraptene with a molecular weight of 298.38. (<b>B</b>) HCCLM3 and HLE cells were plated into a 96-well plate at a density of 20,000 cells/well and treated with the indicated concentrations of auraptene for 24 h. Cell viability was detected with CCK-8 reagent and the IC50 was calculated. (<b>C</b>) HLE and HCCLM3 cells treated with the indicated concentrations of auraptene for 24 h were stained with crystal violet and photographed. (<b>D</b>) HLE and HCCLM3 cells treated with the indicated concentrations of auraptene for 16 h were photographed. Scale bar: 200 μm. (<b>E</b>) HLE and HCCLM3 cells treated with the indicated concentrations of auraptene for 16 h were stained with PI for flow cytometry analysis. Calculated cell death rate (Top) and representative pictures (Bottom) are shown. Aura: Auraptene. (<b>E</b>) Data are represented as the mean ± SD (n = 3), **** <span class="html-italic">p</span> < 0.0001 (one-way ANOVA).</p> "> Figure 2
<p>ROS induction is responsible for auraptene-induced cell growth inhibition and cell death. (<b>A</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene and 5 mM NAC or 5 mM GSH were stained with DCFH-DA for 1 h, followed by flow cytometry analysis. The calculated relative cellular ROS levels (Top) and histogram of flow cytometric pictures are shown (Bottom). (<b>B</b>) The cell viability of HCCLM3 and HLE cells treated with or without 100 μM auraptene, 5 mM NAC, or 5 mM GSH for 24 h was analyzed with CCK-8. (<b>C</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 5 mM NAC or 5 mM GSH for 24 h were stained with crystal violet and the photographs are shown. (<b>D</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 5 mM NAC, or 5 mM GSH for 16 h were photographed and the representative images are shown. Scale bar: 200 μm. (<b>E</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 5 mM NAC, or 5 mM GSH for 16 h were harvested and stained with 10 μg/mL PI followed by flow cytometry analysis. Calculated cell death rate (left) and representative flow cytometric pictures (right) are shown. (<b>A</b>,<b>B</b>,<b>E</b>) Data are represented as the mean ± SD (n = 3); ** <span class="html-italic">p</span> < 0.01, **** <span class="html-italic">p</span> < 0.0001 (one-way ANOVA).</p> "> Figure 3
<p>Auraptene induces HCC cell ferroptosis. (<b>A</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 2 μM Fer-1, or 50 μM DFO for 4 h were incubated with the ROS probe DCFH-DA for 1 h followed by flow cytometry analysis. The calculated total ROS levels (Top) and histogram of flow cytometric pictures (Bottom) are shown. (<b>B</b>) HCCLM3 and HLE cells treated with or without auraptene (100 μM) for 10 h were incubated with lipid ROS probe C11-BODIPY 581/591 for 1 h followed by flow cytometry analysis. The calculated lipid ROS levels (Top) and histogram of flow cytometric pictures (Bottom) are shown. (<b>C</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 2 μM Fer-1, or 50 μM DFO for 24 h were stained with crystal violet and photographed; the images are shown. (<b>D</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 2 μM Fer-1 or 50 μM DFO for 24 h were incubated with CCK-8 followed by an analysis with a microplate reader. (<b>E</b>,<b>F</b>) HCCLM3 and HLE cells treated with or without 100 μM auraptene, 2 μM Fer-1 or 50 μM DFO for 16 h were photographed. Scale bar: 200 μm. (<b>E</b>) or stained with PI followed by analysis with flow cytometry. (<b>F</b>) The calculated cell death rate (<b>F</b>, <b>Top</b>) and the representative flow cytometric pictures (<b>F</b>, <b>Bottom</b>) are shown. (<b>A</b>,<b>B</b>,<b>D</b>,<b>F</b>) Data are represented as the mean ± SD (n = 3); *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001 (Unpaired Student’s <span class="html-italic">t</span> test for (<b>B</b>) and one-way ANOVA for (<b>A</b>,<b>D</b>,<b>F</b>)).</p> "> Figure 4
<p>A low dose of auraptene sensitizes HCC cells to ferroptosis. (<b>A</b>) HCCLM3 and HLE cells treated with or without the indicated concentrations of auraptene, RSL3 (2 μM) for 24 h, or cystine deprivation for 36 h were stained with crystal violet and photographed; the images are shown. (<b>B</b>) HCCLM3 and HLE cells treated with or without the indicated concentrations of auraptene, RSL3 (2 μM) for 24 h, or cystine deprivation for 36 h were photographed and the representative images are shown. Scale bar: 200 μm. (<b>C</b>) HCCLM3 and HLE cells treated with or without indicated concentration of auraptene or RSL3 (2 μM) for 24 h were stained with PI followed by flow cytometry analysis. The calculated cell death rate (left) and the representative flow cytometric pictures (right) are shown. (<b>D</b>) HCCLM3 and HLE cells treated with or without the indicated concentrations of auraptene or cystine deprivation for 36 h were stained with PI followed by flow cytometry analysis. The calculated cell death rate (left) and the representative flow cytometric pictures (right) are shown. (<b>C</b>,<b>D</b>) Data are represented as the mean ± SD (n = 3); ns: no significance, ** <span class="html-italic">p</span> < 0.01, **** <span class="html-italic">p</span> < 0.0001 (one-way ANOVA).</p> "> Figure 5
<p>Auraptene degrades SLC7A11. (<b>A</b>) HCCLM3 and HLE cells treated with indicated concentrations of auraptene for 10 h were harvested for WB analysis with indicated antibodies, with Vinculin as the loading control. (<b>B</b>) HLE cells treated with 100 μM auraptene at the indicated time points were harvested for WB analysis with indicated antibodies, with Vinculin as the loading control. (<b>C</b>) HLE cells were pretreated with 100 μM auraptene for 2 h and then treated with or without CHX (100 μg/mL) or MG132 (10 μM) for another 8 h, then cells were harvested for WB analysis with indicated antibodies. (<b>A</b>–<b>C</b>) The data of SLC7A11/Vinculin are represented as the mean ± SD (n = 3); ns: no significance, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001 (one-way ANOVA). (<b>D</b>) HLE cells were transfected with the specified plasmids for 15 h and then treated with or without 100 μM auraptene for 10 h. Cells were lysed for immunoprecipitated with anti-flag antibodies followed by Western blotting with the specified antibodies. (<b>E</b>) HCCLM3 and HLE cells were treated with or without 100 μM auraptene for 10 h and the cellular GSH levels were determined by a microplate reader at 412 nm. Data are represented as the mean ± SD (n = 3); **** <span class="html-italic">p</span> < 0.0001 (Unpaired Student’s <span class="html-italic">t</span> test).</p> "> Figure 6
<p>The working model of auraptene in HCC ferroptosis induction. Auraptene, the major coumarin of citrus plants, targets SLC7A11 for ubiquitin–proteasomal degradation, leading to lipid ROS production and ferroptosis of HCC. Ub: ubiquitin.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines and Cell Culture
2.2. Reagents and Antibodies
2.3. Cell Viability Assay
2.4. Colony Formation Assay
2.5. Cell Death Analysis
2.6. ROS and Lipid ROS Levels Detection
2.7. Western Blot
2.8. Measurement of Glutathione (GSH)
2.9. Statistical Analysis
3. Results
3.1. Auraptene Exerts Anti-Tumor Effects in HCC Cells
3.2. ROS Induction Is Responsible for Auraptene-Induced Cell Growth Inhibition and Cell Death
3.3. Auraptene Induces HCC Cell Ferroptosis
3.4. A Low Dose of Auraptene Sensitizes HCC Cells to Ferroptosis
3.5. Auraptene Degrades SLC7A11
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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Li, D.; Li, Y.; Chen, L.; Gao, C.; Dai, B.; Yu, W.; Yang, H.; Pi, J.; Bian, X. Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis. Antioxidants 2024, 13, 1015. https://doi.org/10.3390/antiox13081015
Li D, Li Y, Chen L, Gao C, Dai B, Yu W, Yang H, Pi J, Bian X. Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis. Antioxidants. 2024; 13(8):1015. https://doi.org/10.3390/antiox13081015
Chicago/Turabian StyleLi, Donglin, Yingping Li, Liangjie Chen, Chengchang Gao, Bolei Dai, Wenjia Yu, Haoying Yang, Junxiang Pi, and Xueli Bian. 2024. "Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis" Antioxidants 13, no. 8: 1015. https://doi.org/10.3390/antiox13081015
APA StyleLi, D., Li, Y., Chen, L., Gao, C., Dai, B., Yu, W., Yang, H., Pi, J., & Bian, X. (2024). Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis. Antioxidants, 13(8), 1015. https://doi.org/10.3390/antiox13081015