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Tazarotene Induces Apoptosis in Human Basal Cell Carcinoma via Activation of Caspase-8/t-Bid and the Reactive Oxygen Species-Dependent Mitochondrial Pathway

By Chieh-Shan Wu, Gwo-Shing Chen, Ping-Yi Lin, I-Hong Pan, San-Tang Wang, Sheng Hao Lin, Hsin-Su Yu and Chi-Chen Lin


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

Topics: Apoptosis, BH3 Interacting Domain Death Agonist Protein, Carcinoma, Basal Cell, Caspase 3, Caspase 8, Caspase 9, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cytochromes c, Down-Regulation, Enzyme Activation, Fas-Associated Death Domain Protein, G1 Phase Cell Cycle Checkpoints, Humans, In Situ Nick-End Labeling, Inhibitor of Apoptosis Proteins, Keratolytic Agents, Membrane Potential, Mitochondrial, Mitochondria, Nicotinic Acids, Poly(ADP-ribose) Polymerases, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Receptors, Death Domain, Signal Transduction, Skin Neoplasms, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Year: 2015
DOI identifier: 10.1089/dna.2014.2366
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