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

Moon, Hyeongsun, Ruelcke, Jayde E., Choi, Eunju, Sharpe, Laura J., Nassar, Zeyad D., Bielefeldt-ohmann, Helle, Parat, Marie-Odile, Shah, Anup, Francois, Mathias, Inder, Kerry L., Brown, Andrew J., Russell, Pamela J., Parton, Robert G. and Hill, Michelle M. (2015) Diet-induced hypercholesterolemia promotes androgenindependent prostate cancer metastasis via IQGAP1 and caveolin-1. Oncotarget, 6 10: 7438-7453.

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Author Moon, Hyeongsun
Ruelcke, Jayde E.
Choi, Eunju
Sharpe, Laura J.
Nassar, Zeyad D.
Bielefeldt-ohmann, Helle
Parat, Marie-Odile
Shah, Anup
Francois, Mathias
Inder, Kerry L.
Brown, Andrew J.
Russell, Pamela J.
Parton, Robert G.
Hill, Michelle M.
Title Diet-induced hypercholesterolemia promotes androgenindependent prostate cancer metastasis via IQGAP1 and caveolin-1
Journal name Oncotarget   Check publisher's open access policy
ISSN 1949-2553
Publication date 2015-01-01
Sub-type Article (original research)
Open Access Status File (Author Post-print)
Volume 6
Issue 10
Start page 7438
End page 7453
Total pages 16
Place of publication Albany, NY, United States
Publisher Impact Journals
Language eng
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.
Keyword Caveolin-1
Hypercholesterolemia
IQGAP1
Metastasis
Prostate cancer
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes www.impactjournals.com/oncotarget

 
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Created: Fri, 27 Mar 2015, 23:03:21 EST by Charna Kovacevic on behalf of School of Pharmacy