Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1
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Hyeongsun Moon1, Jayde E. Ruelcke1, Eunju Choi1,2,7, Laura J. Sharpe3, Zeyad D. Nassar4, Helle Bielefeldt-Ohmann2, Marie-Odile Parat4, Anup Shah1, Mathias Francois5, Kerry L. Inder1, Andrew J. Brown3, Pamela J. Russell6, Robert G. Parton5 and Michelle M. Hill1
1 The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
2 School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia
3 School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia
4 The School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
5 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
6 Australian Prostate Cancer Research Centre–Queensland and Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Translational Research Institute, Brisbane, QLD, Australia
7 Current address: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Michelle M. Hill, email:
Keywords: Prostate cancer, hypercholesterolemia, metastasis, IQGAP1, caveolin-1
Received: January 29, 2015 Accepted: February 02, 2015 Published: March 02, 2015
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.
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