title: Tazarotene induces apoptosis in human basal cell carcinoma via activation of caspase-8/t-Bid and the reactive oxygen species-dependent mitochondrial pathway.
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.
authors.affiliation: 1 Department of Dermatology, Kaohsiung Veterans General Hospital , Kaohsiung, Taiwan .
authors.forename: Chieh-Shan
authors.initials: CS
authors.lastname: Wu
authors.forename: Gwo-Shing
authors.initials: GS
authors.lastname: Chen
authors.forename: Ping-Yi
authors.initials: PY
authors.lastname: Lin
authors.forename: I-Hong
authors.initials: IH
authors.lastname: Pan
authors.forename: San-Tang
authors.initials: ST
authors.lastname: Wang
authors.forename: Sheng Hao
authors.initials: SH
authors.lastname: Lin
authors.forename: Hsin-Su
authors.initials: HS
authors.lastname: Yu
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein / Q000235:genetics; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D007641:Keratolytic Agents / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis; D012176:Retinoids
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D045304:Cytochromes c; D053200:Fas-Associated Death Domain Protein; D051034:Inhibitor of Apoptosis Proteins; D007641:Keratolytic Agents; D009539:Nicotinic Acids; D011065:Poly(ADP-ribose) Polymerases; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; C494814:BID protein, human; C107489:BIRC5 protein, human; C496866:XIAP protein, human; C086827:tazarotene; D012176:Retinoids