LCL-161

Fragile X Mental Retardation Protein 1 (FMR1) is a translational repressor crucial for regulating genes in the central nervous system. While a lack of FMR1 expression causes Fragile X Syndrome (FXS), its overexpression is implicated in various cancers, necessitating tight regulation of FMR1 protein levels for normal cell physiology. In this study, we report that FMR1 is upregulated in gastric cancer patients. Reducing FMR1 expression decreased cell growth in gastric cancer cell lines. The Smac Mimetic LCL161 reduced both FMR1 and cellular inhibitor of apoptosis protein 2 (cIAP2) levels. Suppressing cIAP2, but not cIAP1, led to decreased FMR1, while cIAP2 overexpression increased FMR1 in gastric cancer cells. We observed that cIAP2 is also upregulated in gastric cancer patients, with FMR1 and cIAP2 levels positively correlated in both gastric and colorectal cancers. Notably, cIAP2 binds FMR1 via its CARD domain, unlike most cIAP2 targets that bind the BIR domain. Furthermore, cIAP2 ubiquitinates FMR1 through its CARD-RING domains, stabilizing the protein without proteasomal degradation. FMR1, modulated by cIAP2, promotes gastric cancer cell growth. Collectively, our findings highlight FMR1's growth-promoting role in gastric cancer and reveal a novel function of cIAP2 in stabilizing FMR1 as an E3 ligase. These results suggest targeting cIAP2 could be an effective strategy for treating gastric cancer by downregulating both cIAP2 and FMR1.