Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy

Abstract

Background: Several studies had suggested the potential role of calcium signaling in prostate cancer (PCa) prognosis and agressiveness. We aimed to investigate selected proteins contributing to calcium (Ca2+) signaling, (Orai, stromal interaction molecule (STIM), and transient receptor potential (TRP) channels) and involved in cancer hallmarks, as independent predictors of systemic recurrence after radical prostatectomy (RP). Methods: A case‐control study including 112 patients with clinically localized PCa treated by RP between 2002 and 2009 and with at least 6‐years’ follow‐up. Patients were divided into two groups according to the absence or presence of systemic recurrence. Expression levels of 10 proteins involved in Ca2+ signaling (TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, STIM1, STIM2, Orai1, Orai2, and Orai3), were assessed by immunohistochemistry using tissue microarrays (TMAs) constructed from paraffin‐embedded PCa specimens. The level of expression of the various transcripts in PCa was assessed using quantitative polymerase chain reaction (qPCR) analysis. RNA samples for qPCR were obtained from fresh frozen tissue samples of PCa after laser capture microdissection on RP specimens. Relative gene expression was analyzed using the 2−▵▵Ct method. Results: Multivariate analysis showed that increased expression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 was significantly associated with a lower risk of systemic recurrence after RP, independently of the prostate‐specific antigen (PSA) level, percentage of positive biopsies, and surgical margin (SM) status (P = .007, P = .01, P < .001, P = .0065, P = .007, and P = .01, respectively). For TRPC4, TRPV5, and TRPV6, this association was also independent of Gleason score and pT stage. Moreover, overexpression of TRPV6 and Orai2 was significantly associated with longer time to recurrence after RP (P = .048 and .023, respectively). Overexpression of TRPC4, TRPV5, TRPV6, and Orai2 transcripts was observed in group R− (3.71‐, 5.7‐, 1.14‐, and 2.65‐fold increase, respectively). Conclusions: This is the first study to suggest the independent prognostic value of certain proteins involved in Ca2+ influx in systemic recurrence after RP: overexpression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 is associated with a lower risk of systemic recurrence. TRPC4, TRPV5, and TRPV6 appear to be particularly interesting, as they are independent of the five commonly used predictive factors, that is, PSA, percentage of positive biopsies, SM status, Gleason score, and pT stage.

The TRPC1 Channel Forms a PI3K/CaM Complex and Regulates Pancreatic Ductal Adenocarcinoma Cell Proliferation in a Ca2+-Independent Manner

“…In addition, our findings show that the high expression of TRPC1 correlated with low overall survival in PDAC patients. However, the dysregulated expression of TRPC1 will remain controversial and seems to be cell type-specific, as the upregulation of TRPC1 appears to have a protective role in prostate [ 51 , 52 ] and some breast cancer patients [ 33 ]. Consistent with the increased TRPC1 mRNA expression, TRPC1 protein expression also significantly increased in human PDAC samples, where TRPC1 localizes to the plasma membrane, compared to adjacent non-tumor tissue, where it localizes in the cytoplasmic compartments.…”

TRPC Channels in the SOCE Scenario

“…STIM1-Orai1-TRPC1-mediated Ca 2+ entry is also required for platelet aggregation [72], insulin release [73], adipocyte differentiation and adiponectin secretion [74], among other functions. Moreover, STIM1-Orai1-TRPC1-dependent Ca 2+ currents have been associated to the Ca 2+ mobilization responsible for the development of distinct cancer hallmarks in different cancer cell types, including prostate cancer cells [75] and colon cancer cells [76,77], while STIM1-Orai1-TRPC1-TRPC4-mediated Ca 2+ currents are involved in the Ca 2+ remodelling involved in hypertrophic cardiomyopathy in rat ventricular myocytes [78]. A more recent study has reported that in anterior pituitary (AP) cells from Orai1-lacking mice TG-induced SOCE as well as Ca 2+ entry evoked by TRH and LHRH were impaired, by contrast, SOCE was unaffected in AP cells from mice lacking expression of all seven TRPC channels, although spontaneous intracellular Ca 2+ -oscillations associated to electrical activity as well as Ca 2+ responses to TRH and GHRH were significantly reduced in the absence of TRPC channels, thus suggesting that SOCE might function independently of TRPC channels and that Orai1 and TRPC channels, such as TRPC1, might play different functional roles [79].…”

TRPM8 Channels and SOCE: Modulatory Crosstalk between Na+ and Ca2+ Signaling

“…Additionally, Zhang demonstrated that both the G protein-coupled receptor (GPCR) Gα q -subunit and PIP 2 were able to inhibit TRPM8 channels, and the TRPM8-Gα q binding impaired Gα q coupling and signaling to PLCβ-PIP 2 [60]. In this way, multivariate analysis showed that overexpression of TRPM8, and STIM2 is associated with a lower risk of systemic recurrence after radical prostatectomy [61]. Taken together, these studies suggest that Gα q -subunit and PLCβ-PIP 2 generating IP 3 could be a novel insight to further understand the structure-function relationships of TRPM8 and SOCE.…”