title: FGFR3 stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth.
abstract: Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of receptor tyrosine kinases that control cell proliferation, differentiation, and survival. Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. Through transcriptional profiling of bladder carcinoma cells subjected to short hairpin RNA knockdown of FGFR3, we identified a gene-signature linking FGFR3 signaling with de novo sterol and lipid biosynthesis and metabolism. We found that FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, sterol regulatory element-binding protein 1(SREBP1/SREBF1), in a PI3K-mTORC1-dependent fashion. In turn, SREBP1 regulates the expression of key lipogenic enzymes, including stearoyl CoA desaturase 1 (SCD1/SCD). SCD1 is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids and is crucial for lipid homeostasis. In human bladder cancer cell lines expressing constitutively active FGFR3, knockdown of SCD1 by siRNA markedly attenuated cell-cycle progression, reduced proliferation, and induced apoptosis. Furthermore, inducible knockdown of SCD1 in a bladder cancer xenograft model substantially inhibited tumor progression. Pharmacologic inhibition of SCD1 blocked fatty acid desaturation and also exerted antitumor activity in vitro and in vivo. Together, these findings reveal a previously unrecognized role of FGFR3 in regulating lipid metabolism to maintain tumor growth and survival, and also identify SCD1 as a potential therapeutic target for FGFR3-driven bladder cancer.
authors.affiliation: Molecular Oncology, Cancer Signaling and Translational Oncology, Bioinformatics, and Pathology, Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Du
authors.forename: Qian-Rena
authors.initials: QR
authors.lastname: Wang
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Dorothy
authors.initials: D
authors.lastname: French
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Jing
authors.initials: J
authors.lastname: Qing
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004318:Doxycycline; D005227:Fatty Acids; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051498:Receptor, Fibroblast Growth Factor, Type 3; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D058570:TOR Serine-Threonine Kinases; C497387:SREBF1 protein, human; C523776:SCD1 protein, human; C496365:FGFR3 protein, human