cytochrome-c-t and tazarotene

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; bcl-X Protein; 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; Reactive Oxygen Species; Receptors, Death Domain; RNA Interference; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Survivin; X-Linked Inhibitor of Apoptosis Protein