Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer
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Theodoros Karantanos1,4,*, Styliani Karanika1,5,*, Jianxiang Wang1, Guang Yang1, Masato Dobashi1, Sanghee Park1, Chengzhen Ren1, Likun Li1, Spyridon P. Basourakos1, Anh Hoang1, Eleni Efstathiou1, Xuemei Wang3, Patricia Troncoso2, Mark Titus1, Bradley Broom3, Jeri Kim1, Paul G. Corn1, Christopher J. Logothetis1, Timothy C. Thompson1
1Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
4Current address: General Internal Medicine Section, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA
5Current address: Infectious Diseases Division, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA
*These authors have contributed equally to this work
Timothy C. Thompson, email: firstname.lastname@example.org.
Keywords: prostate cancer, caveolin-1, lipid synthesis, mCRPC, FASN
Received: May 16, 2016 Accepted: June 03, 2016 Published: June 16, 2016
Caveolin-1 (Cav-1) is overexpressed in aggressive and metastatic prostate cancer (PCa) and induces PCa cell proliferation. Androgens mediate lipid synthesis through acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN). We investigated the Cav-1-mediated lipid synthesis in the development of castration resistance, and identified novel therapeutic opportunities. Using the PBCre+;Ptenloxp/loxp;PBCav-1+ mouse model we found that Cav-1 induction increased cancer incidence and growth, and ACC1-FASN expression in intact and castrated mice. We demonstrated that Cav-1 regulated ACC1 and FASN expression in an AR-independent way and increased palmitate synthesis using western blot analysis, qRT-PCR and mass spectrometry in vitro. By using FASN siRNA and C-75, we found that FASN inhibition was more effective in Cav-1-overexpressing cells. This inhibition was abrogated by ACC1si RNA, revealing the role of malonyl-CoA, an ACC1 product, as a mediator of cytotoxicity. Cav-1 was associated with ACC1 in human tumors and ACC1, FASN, and Cav-1 expression were increased in metastatic PCa compared to primary tumors and normal prostate epithelium. Palmitoleate and oleate levels were higher in BMA from patients with metastatic PCa who responded poorly to abiraterone acetate. Our findings suggest that Cav-1 promotes hormone resistance through the upregulation of ACC1-FASN and lipid synthesis under androgen deprivation, suggesting that FASN inhibition could be used to treat PCa that demonstrates Cav-1 overexpression.
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