title: Squamous cell carcinoma antigen 1 promotes caspase-8-mediated apoptosis in response to endoplasmic reticulum stress while inhibiting necrosis induced by lysosomal injury.
abstract: Squamous cell carcinoma antigen 1 (SCCA1) is a member of the serine protease inhibitor (serpin) family of proteins, whose target proteases include the cathepsins. Initially identified as a serological marker for advanced squamous cell carcinomas of the cervix, SCCA1 has also been found to be associated with other cancer types of epithelial or endodermal origins such as lung cancer, head and neck cancer, melanoma, and hepatocellular carcinoma. While the biological function of SCCA1 remains largely unclear, it is believed to limit cellular damage resulting from lysosomal cathepsin release. Here, we show that SCCA1 acts as a molecular switch that inhibits cell death induced by lysosomal injury resulting from DNA alkylating agents and hypotonic shock, whereas it promotes a caspase-8-mediated apoptosis in response to endoplasmic reticulum (ER) stress. In response to ER stress, SCCA1 blocks both lysosomal and proteasomal protein degradation pathways and enhances the interaction between sequestosome 1/p62 and caspase-8, which leads to the aggregation of intracellular caspase-8 and its subsequent cleavage and activation. Hence, on one hand, SCCA1 inhibits cell death induced by lysosomal injury while, on the other hand, it sensitizes cells to ER stress by activating caspase-8 independently of the death receptor apoptotic pathway.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794-5222, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Ullman
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Pan
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D014415:Tunicamycin / Q000378:metabolism; D054875:Ubiquitination; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D000951:Antigens, Neoplasm; C494773:Bak1 protein, mouse; D005456:Fluorescent Dyes; D015843:Serpins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C051072:squamous cell carcinoma-related antigen; D014415:Tunicamycin; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex