title: Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation.
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.
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bernichtein
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.
authors.forename: Natascha
authors.initials: N
authors.lastname: Pigat
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.|Urology Department, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barry Delongchamps
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Boutillon
authors.affiliation: Pathology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.affiliation: Centre de Pathologie, Amiens, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Camparo
authors.affiliation: Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'anatomo-cytopathologie, Inserm, IMRB U955-E10, Université Paris-Est, Maisons-Alfort, Paris, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Reyes-Gomez
authors.affiliation: Urology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Méjean
authors.affiliation: Medical Oncology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Stéphane M
authors.initials: SM
authors.lastname: Oudard
authors.affiliation: Institute for European Expertise in Physiology, Paris, France.
authors.forename: Eve M
authors.initials: EM
authors.lastname: Lepicard
authors.affiliation: Institute for European Expertise in Physiology, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Viltard
authors.affiliation: Physiology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Souberbielle
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Friedlander
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Capiod
authors.affiliation: Inserm Unit 1151, Institut Necker Enfants Malades (INEM), Université Paris Descartes, Paris, France. vincent.goffin@inserm.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
mesh_terms: D000818:Animals; D002118:Calcium / Q000633:toxicity*; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology*; D004032:Diet / Q000009:adverse effects*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000473:pathology*; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D015854:Up-Regulation
chemical_list: D044169:Receptors, Calcium-Sensing; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D002762:Cholecalciferol; D002118:Calcium