Oncotarget

Research Papers:

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

Theodoros Karantanos, Styliani Karanika, Jianxiang Wang, Guang Yang, Masato Dobashi, Sanghee Park, Chengzhen Ren, Likun Li, Spyridon P. Basourakos, Anh Hoang, Eleni Efstathiou, Xuemei Wang, Patricia Troncoso, Mark Titus, Bradley Broom, Jeri Kim, Paul G. Corn, Christopher J. Logothetis and Timothy C. Thompson _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:46321-46334. https://doi.org/10.18632/oncotarget.10113

Metrics: PDF 1913 views  |   HTML 1593 views  |   ?  


Abstract

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

Correspondence to:

Timothy C. Thompson, email: timthomp@mdanderson.org.

Keywords: prostate cancer, caveolin-1, lipid synthesis, mCRPC, FASN

Received: May 16, 2016    Accepted: June 03, 2016    Published: June 16, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10113