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 Ca 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.

Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

“…Thus, targeting TRPC6 channel function may be a viable approach to treat gastric cancer. Over the past decades, very few small molecular TRPC6 antagonists [15,16,25,27–32] (examples shown in Chart 1) have been reported, and some of them have shown strong growth-inhibitory effects on cancer both in vitro and in vivo . Among them, vitamin D3 effectively reduced calcium-induced early-stage prostate tumorigenesis by down-regulating TRPC6 and the calcium sensing receptor both in vitro and in vivo [25].…”

“…Over the past decades, very few small molecular TRPC6 antagonists [15,16,25,27–32] (examples shown in Chart 1) have been reported, and some of them have shown strong growth-inhibitory effects on cancer both in vitro and in vivo . Among them, vitamin D3 effectively reduced calcium-induced early-stage prostate tumorigenesis by down-regulating TRPC6 and the calcium sensing receptor both in vitro and in vivo [25]. The use of SKF96365, albeit being nonspecific, supported the results from siRNA silencing on the essential roles of TRPC6 channels in G2/M phase progression of gastric cancer cells and tumor formation in the xenograft model [27].…”

Role of Vitamin D and Risk of prostate cancer

“…Chronic inflammation promotes metastases and progression to castration-resistant prostate cancer [11,12]. CRP could predict tumor aggressiveness and potential treatment efficacy in patients with prostate cancer [13].…”

Ion Channel Regulation by Sex Steroid Hormones and Vitamin D in Cancer: A Potential Opportunity for Cancer Diagnosis and Therapy

“…Data strongly suggested that the antitumor effect of vitamin D and calcitriol included a transcriptional down-regulation of TRPC6 calcium channels. Moreover, the proliferation of PC-3 prostate cancer cells was decreased by silencing the expression of TRPC6 (Bernichtein et al, 2017). Khatun et al, (2016) showed that calcitriol (1 uM, 72 h) and calcipotriol (1 uM, 72 h), a VDR agonist, inhibited the expression of KCa1.1 channels in MDA-MB-453 breast cancer cells.…”