Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1.
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.
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Hyeongsun
H
Moon
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Jayde E
JE
Ruelcke
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.|School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia.|Current address: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Eunju
E
Choi
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
Laura J
LJ
Sharpe
The School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia.
Zeyad D
ZD
Nassar
School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia.
Helle
H
Bielefeldt-Ohmann
The School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia.
Marie-Odile
MO
Parat
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Anup
A
Shah
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
Mathias
M
Francois
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Kerry L
KL
Inder
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
Andrew J
AJ
Brown
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.
Pamela J
PJ
Russell
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
Robert G
RG
Parton
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Michelle M
MM
Hill
D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000473:pathology*; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
D051242:Caveolin 1; C101203:IQ motif containing GTPase activating protein 1; D020703:ras GTPase-Activating Proteins
IQGAP1; caveolin-1; hypercholesterolemia; metastasis; prostate cancer