Tazarotene induces apoptosis in human basal cell carcinoma via activation of caspase-8/t-Bid and the reactive oxygen species-dependent mitochondrial pathway

• Published in: DNA and cell biology Vol. 33; no. 10; p. 652
• Main Authors: Wu, Chieh-Shan, Chen, Gwo-Shing, Lin, Ping-Yi, Pan, I-Hong, Wang, San-Tang, Lin, Sheng Hao, Yu, Hsin-Su, Lin, Chi-Chen
• Format: Journal Article
• Language: English
• Published: United States 01.10.2014
• Subjects: Apoptosis - drug effects; bcl-X Protein - biosynthesis; BH3 Interacting Domain Death Agonist Protein - metabolism; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - pathology; Caspase 3 - metabolism; Caspase 8 - metabolism; Caspase 9 - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytochromes c - secretion; Down-Regulation - drug effects; Enzyme Activation - drug effects; Fas-Associated Death Domain Protein - genetics; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; In Situ Nick-End Labeling; Inhibitor of Apoptosis Proteins - biosynthesis; Keratolytic Agents - pharmacology; Membrane Potential, Mitochondrial - drug effects; Mitochondria - metabolism; Nicotinic Acids - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Reactive Oxygen Species; Receptors, Death Domain - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction - drug effects; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; X-Linked Inhibitor of Apoptosis Protein - biosynthesis
• ISSN: 1557-7430
• DOI: 10.1089/dna.2014.2366

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.