FGFR3 Stimulates Stearoyl CoA Desaturase 1 Activity to Promote Bladder Tumor Growth

摘要: Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of tyrosine kinases that control cell proliferation, differentiation, and survival. Aberrant activation FGFR3 via overexpression or mutation is frequent feature bladder cancer; however, its molecular cellular consequences functional relevance carcinogenesis are not well understood. Through transcriptional profiling carcinoma cells subjected short hairpin RNA knockdown FGFR3, we identified gene-signature linking signaling with de novo sterol lipid biosynthesis metabolism. We found promotes the cleavage master regulator lipogenesis, regulatory element-binding protein 1(SREBP1/SREBF1), in PI3K-mTORC1-dependent fashion. In turn, SREBP1 regulates expression key lipogenic enzymes, including stearoyl CoA desaturase 1 (SCD1/SCD). SCD1 rate-limiting enzyme monounsaturated fatty acids crucial for homeostasis. human cancer lines expressing constitutively active by siRNA markedly attenuated cell-cycle progression, reduced induced apoptosis. Furthermore, inducible xenograft model substantially inhibited tumor progression. Pharmacologic inhibition blocked acid desaturation also exerted antitumor activity vitro vivo. Together, these findings reveal previously unrecognized role regulating metabolism maintain survival, identify as potential therapeutic target FGFR3-driven cancer.