title: SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds.
abstract: Smac mimetic compounds (SMCs) are experimental small molecules that induce tumour necrosis factor alpha (TNFα)-dependent cancer cell death by targeting the inhibitor of apoptosis proteins. However, many cancer cell lines are resistant to SMC-mediated apoptosis despite the presence of TNFα. To add insight into the mechanism of SMC-resistance, we used functional siRNA-based kinomic and focused chemical screens and identified suppressor of morphogenesis in genitalia-1 (SMG1) and NF-κB-inducing kinase (NIK) as novel protective factors. Both SMG1 and NIK prevent SMC-mediated apoptosis likely by maintaining FLICE inhibitory protein (c-FLIP) levels to suppress caspase-8 activation. In SMC-resistant cells, the accumulation of NIK upon SMC treatment enhanced the activity of both the classical and alternative nuclear factor-κB pathways, and increased c-FLIP mRNA levels. In parallel, persistent SMG1 expression in SMC-resistant cells repressed SMC-mediated TNFα-induced JNK activation and c-FLIP levels were sustained. Importantly, SMC-resistance is overcome by depleting NIK and SMG1, which appear to facilitate the downregulation of c-FLIP in response to SMC and TNFα treatment, leading to caspase-8-dependent apoptosis. Collectively, these data show that SMG1 and NIK function as critical repressors of SMC-mediated apoptosis by potentially converging on the regulation of c-FLIP metabolism.
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada. herman@arc.cheo.ca
authors.forename: H H
authors.initials: HH
authors.lastname: Cheung
authors.forename: M
authors.initials: M
authors.lastname: St Jean
authors.forename: S T
authors.initials: ST
authors.lastname: Beug
authors.forename: R
authors.initials: R
authors.lastname: Lejmi-Mrad
authors.forename: E
authors.initials: E
authors.lastname: LaCasse
authors.forename: S D
authors.initials: SD
authors.lastname: Baird
authors.forename: D F
authors.initials: DF
authors.lastname: Stojdl
authors.forename: R A
authors.initials: RA
authors.lastname: Screaton
authors.forename: R G
authors.initials: RG
authors.lastname: Korneluk
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C514704:SMG1 protein, human