TY - JOUR
T1 - Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer
AU - Karantanos, Theodoros
AU - Karanika, Styliani
AU - Wang, Jianxiang
AU - Yang, Guang
AU - Dobashi, Masato
AU - Park, Sanghee
AU - Ren, Chengzhen
AU - Li, Likun
AU - Basourakos, Spyridon P.
AU - Hoang, Anh
AU - Efstathiou, Eleni
AU - Wang, Xuemei
AU - Troncoso, Patricia
AU - Titus, Mark
AU - Broom, Bradley
AU - Kim, Jeri
AU - Corn, Paul G.
AU - Logothetis, Christopher J.
AU - Thompson, Timothy C.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Caveolin-1
KW - FASN
KW - Lipid synthesis
KW - MCRPC
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=84979917735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979917735&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10113
DO - 10.18632/oncotarget.10113
M3 - Article
C2 - 27331874
AN - SCOPUS:84979917735
SN - 1949-2553
VL - 7
SP - 46321
EP - 46334
JO - Oncotarget
JF - Oncotarget
IS - 29
ER -