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Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation

Authors :
Jean-Claude Souberbielle
Thierry Capiod
Arnaud Mejean
Stéphane Oudard
Nicolas Barry Delongchamps
Edouard Reyes-Gomez
Florence Boutillon
Natascha Pigat
Mélanie Viltard
Virginie Verkarre
Eve M. Lepicard
Vincent Goffin
Sophie Bernichtein
Philippe Camparo
Gérard Friedlander
Source :
Cancer Research. 77:355-365
Publication Year :
2017
Publisher :
American Association for Cancer Research (AACR), 2017.

Abstract

Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355–65. ©2016 AACR.

Details

ISSN :
15387445 and 00085472
Volume :
77
Database :
OpenAIRE
Journal :
Cancer Research
Accession number :
edsair.doi.dedup.....0be953b224070f1a13e5a5a0d80b5e3d