Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1

Hyeongsun Moon, Jayde E. Ruelcke, Eun ju Choi, Laura J. Sharpe, Zeyad D. Nassar, Helle Bielefeldt-Ohmann, Marie Odile Parat, Anup Shah, Mathias Francois, Kerry L. Inder, Andrew J. Brown, Pamela J. Russell, Robert G. Parton, Michelle M. Hill

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.

Original languageEnglish (US)
Pages (from-to)7438-7453
Number of pages16
JournalOncotarget
Volume6
Issue number10
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Caveolin-1
  • Hypercholesterolemia
  • IQGAP1
  • Metastasis
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Moon, H., Ruelcke, J. E., Choi, E. J., Sharpe, L. J., Nassar, Z. D., Bielefeldt-Ohmann, H., Parat, M. O., Shah, A., Francois, M., Inder, K. L., Brown, A. J., Russell, P. J., Parton, R. G., & Hill, M. M. (2015). Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1. Oncotarget, 6(10), 7438-7453. https://doi.org/10.18632/oncotarget.3476