title: Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer.
abstract: 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.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.|Current address: General Internal Medicine Section, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Karantanos
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.|Current address: Infectious Diseases Division, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Styliani
authors.initials: S
authors.lastname: Karanika
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Dobashi
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Chengzhen
authors.initials: C
authors.lastname: Ren
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Likun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Spyridon P
authors.initials: SP
authors.lastname: Basourakos
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Titus
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Broom
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Jeri
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Corn
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D008055:Lipids; D054890:Fatty Acid Synthase, Type I; D000103:Acetyl-CoA Carboxylase
keywords: FASN; caveolin-1; lipid synthesis; mCRPC; prostate cancer