Abstract
Previous studies suggest that tazarotene, a new member of the acetylenic class of RARβ/γ selective retinoids which is approved to treat a variety of skin diseases, exhibits an anti-proliferative effect in human basal cell carcinoma (BCC) by triggering caspase-dependent apoptosis. However, the detailed molecular mechanisms underlying the anti-tumor activity of tazarotene are poorly understood. This study aims at investigating the molecular mechanisms of tazarotene-induced apoptosis in human BCC cells. Our results are the first to demonstrate that tazarotene induces mitochondria-dependent cleavage of caspase-9 and -3 and PARP in BCC cells by producing reactive oxygen species (ROS) and activating caspase-8 through both ROS and death receptor signaling. These events are accompanied by a decrease in BCL-2 and BCL-xl anti-apoptotic proteins as well as by survivin and XIAP, two IAP family members. Furthermore, our results presented for the first time that tazarotene triggers a convergence of the intrinsic and extrinsic apoptotic pathways via the caspase-8-truncated Bid signaling pathway. Collectively, these data provide insights into the molecular mechanisms underlying tazarotene-induced apoptosis in human BCC cells, suggesting that this compound is a potential anti-skin cancer drug.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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BH3 Interacting Domain Death Agonist Protein / metabolism
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Carcinoma, Basal Cell / drug therapy*
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Carcinoma, Basal Cell / pathology
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Caspase 3 / metabolism
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Caspase 8 / metabolism*
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Caspase 9 / metabolism
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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Cytochromes c / metabolism
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Down-Regulation / drug effects
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Enzyme Activation / drug effects
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Fas-Associated Death Domain Protein / genetics
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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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In Situ Nick-End Labeling
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Inhibitor of Apoptosis Proteins / biosynthesis
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Keratolytic Agents / pharmacology*
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / metabolism
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Nicotinic Acids / pharmacology*
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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RNA Interference
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RNA, Small Interfering
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Reactive Oxygen Species
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Receptors, Death Domain / metabolism
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Signal Transduction / drug effects
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / pathology
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Survivin
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X-Linked Inhibitor of Apoptosis Protein / biosynthesis
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bcl-X Protein / biosynthesis
Substances
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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BIRC5 protein, human
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Fas-Associated Death Domain Protein
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Inhibitor of Apoptosis Proteins
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Keratolytic Agents
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Nicotinic Acids
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Reactive Oxygen Species
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Receptors, Death Domain
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Survivin
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-X Protein
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tazarotene
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Cytochromes c
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Poly(ADP-ribose) Polymerases
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Caspase 3
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Caspase 8
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Caspase 9