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

American Association for Cancer Research (AACR) - Tập 72 Số 22 - Trang 5843-5855 - 2012
Xiangnan Du1, Qian-Rena Wang1, Emily Chan1, Mark Merchant1, Jinfeng Liu1, Dorothy French1, Avi Ashkenazi1, Jing Qing1
1Authors' Affiliations: 1Molecular Oncology, 2Cancer Signaling and Translational Oncology, 3Bioinformatics, and 4Pathology, Genentech, Inc., South San Francisco, California

Tóm tắt

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. Cancer Res; 72(22); 5843–55. ©2012 AACR.

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American Association for Cancer Research (AACR)

Tập 72 Số 22

5843-5855

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