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.

Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway

“…We found that three of the most highly induced genes after Cud C exposure were EGR1 (Early Response Growth-1), HUWE1 (HECT, UBA and WWE domain containing 1) and SMG1 (Suppressor of morphogenesis in genitalia-1) which have been reported to modulate apoptosis and cell cycle [34–36]. In contrast, Cud C downregulated MYB1 (v-myb avian myeloblastosis viral oncogene homolog), CCNB1 (cyclin B1) and GPX2 (Glutathione peroxidase 2), which have been shown to promote cancer proliferation and metastasis [37–44].…”

Reversal of CYLD phosphorylation as a novel therapeutic approach for adult T-cell leukemia/lymphoma (ATLL)

“…Nonetheless, it is possible for death-signaling CYLD and RIPK1 molecules, activated by disruption of the early checkpoint, to override the protection provided by the second NFκBdependent checkpoint. This is illustrated by SMAC mimetics, which activate the noncanonical NFκB signaling pathway 72,73 . Despite the induction of noncanonical NFκB signaling, which is highly prosurvival 74 , the cells remain vulnerable to CYLD and RIPK1-dependent death in the presence of SMAC mimetics and TNF.…”

Smg1 haploinsufficiency predisposes to tumor formation and inflammation

“…Smg1 knockdown by siRNA decreased survival of myeloma but not control cell lines (29), and SMG1 mRNA has been shown to be up-regulated in acute myeloid leukemia (30). Furthermore, in a number of treatment studies, SMG1 expression or enzymatic activity has been required for an effective response to anticancer treatments, including antioxidant therapy and radiotherapy (31)(32)(33)(34). Combined, these studies suggest that SMG1 may play different roles in cancer progression depending on the stage of disease, the type of cancer, and the therapy used.…”