TRPV6 channel controls prostate cancer cell proliferation via Ca2+/NFAT-dependent pathways

Abstract

The transient receptor potential channel, subfamily V, member 6 (TRPV6), is strongly expressed in advanced prostate cancer and significantly correlates with the Gleason >7 grading, being undetectable in healthy and benign prostate tissues. However, the role of TRPV6 as a highly Ca 2 þ -selective channel in prostate carcinogenesis remains poorly understood. Here, we report that TRPV6 is directly involved in the control of prostate cancer cell (LNCaP cell line) proliferation by decreasing: (i) proliferation rate; (ii) cell accumulation in the S-phase of cell cycle and (iii) proliferating cell nuclear antigen (PCNA) expression. We demonstrate that the Ca 2 þ uptake into LNCaP cells is mediated by TRPV6, with the subsequent downstream activation of the nuclear factor of activated T-cell transcription factor (NFAT). TRPV6-mediated Ca 2 þ entry is also involved in apoptosis resistance of LNCaP cells. Our results suggest that TRPV6 expression in LNCaP cells is regulated by androgen receptor, however, in a ligand-independent manner. We conclude that the upregulation of TRPV6 Ca 2 þ channel in prostate cancer cells may represent a mechanism for maintaining a higher proliferation rate, increasing cell survival and apoptosis resistance as well.

CaV3.2 T-type Calcium Channels Are Involved in Calcium-dependent Secretion of Neuroendocrine Prostate Cancer Cells

“…As can be observed from our experiments, inhibition of CaV3.2 channels by either siRNAs or inhibitors does not totally abolish PAP secretion. This may reflect the participation of other calcium channels in secretion such as TRPV6 channels, which have been shown to be expressed in prostate LNCaP cells and to participate to basal calcium entry (35). In addition, we confirm that T-type calcium channels can be activated by phorbol esters (PMA) as previously shown by others (28).…”

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

“…It has been documented for half a century that low [Ca 2 þ ] induces colon cell proliferation in vitro and in vivo. 46,47 Although several recent studies have shown that TRPV6 overexpression is often associated with increased cell proliferation in colon, breast, and prostate cancers, [48][49][50] it is not clear how an increase in TRPV5/6 levels leads to elevated proliferation. The Ca 2 þ deficiency-induced and Trpv5/6-dependent IGF signaling unraveled by this study provides a possible mechanistic explanation for the elevated epithelial cell proliferation in Ca 2 þ deficiency.…”

Remodelling of Ca2+transport in cancer: how it contributes to cancer hallmarks?

“…Consistent with this notion, it was shown that the proliferation-promoting action of a1-adrenoreceptor (a1-AR) agonists on prostate cancer (PCa) cells is based on preferred coupling of the a1-AR-coupled signalling pathway to activation of a member of transient receptor potential (TRP) channel family, TRPC6, Ca 2þ influx through which in turn specifically regulates NFAT in a Ca 2þ /calcineurin-dependent manner [17]. In addition, in LNCaP PCa cells yet another highly oncogenic TRP member, TRPV6 [18], was shown to support high proliferation rates apparently by providing constitutive Ca 2þ influx required for subsequent downstream NFAT activation [19]. TRPV6 expression in PCa cells is also positively regulated by vitamin D3 receptor (VDR) activation to enhance [Ca 2þ ] C and proliferation of cells [20].…”

“…B 369: 20130097 are number of instances when apoptosis resistance is conferred by higher expression of Ca 2þ entry channels (figure 2). Indeed, it was shown that TRPV6 and ORAI3 not only promote proliferation, but also increase survival of PCa and breast cancer cells, respectively [19,20,24]. ORAI3-conferred survival of breast cancer cells involved Ca 2þ -dependent increase of c-Myc expression and activity resulting in the inhibition of pro-apoptotic Bax protein expression [24,25].…”

“…Many Ca 2þ -transport proteins have been implicated in the proliferation of cancer cells, including sarco(endo)plasmic reticulum (SERCA) [26], the Golgi network secretory pathway (SPCA) [27] and plasma membrane (PMCA) [28] Ca 2þ -ATPases ( pumps), the inositol 1,4,5-trisphosphate receptor (IP 3 R) [29,30] and ryanodine receptor (RyR) [31] [19], TRPC1, TRPC3 and TRPC6 [17,[37][38][39][40], TRPM2 [41], TRPM7 [40,42], TRPM8 [40,43] (figure 1). Enhanced proliferation of cancer cells is commonly correlated with higher expression of those proteins from the Ca 2þ -handling toolkit which participate in [Ca 2þ ] C increases by providing Ca 2þ influx or Ca 2þ release, or which sustain ER Ca 2þ filing.…”