Expression of store-operated channel components in prostate cancer: the prognostic paradox

In vitro studies in prostate cancer (PCa) cell lines have suggested a key and complex role of the store-operated channels (SOCs) in major cancer hallmarks, including proliferation, apoptosis, and migration. In the present study, we investigated in vivo the expression of the SOC components transient receptor potential canonical (TRPC) 1, TRPC4, Orai1, and stromal interaction molecule 1 (STIM1), during all stages of PCa progression, and evaluated their prognostic impact in clinically localized cancer (CLC). The expressions of TRPC1, TRPC4, Orai1, STIM1, and the androgen receptor and the proliferation marker Ki-67 were evaluated by immunohistochemistry on tissue microarrays containing samples of normal prostate tissues (n=91), prostatic intraepithelial neoplasia (n=61), CLC surgically treated (n=238), and castration-resistant prostate cancer (CRPC; n=45). All markers significantly increased in CLC compared with normal tissues and (for Orai1 and STIM1) in advanced pT3 tumors compared with pT2. In contrast, their expression decreased in CRPC, particularly for Orai1. In CLC, staining for TRPC1, Orai1 and STIM1 correlated with androgen receptor expression, and TRPC1 status was associated with lower proliferation and longer recurrence-free survival, after adjusting for classical prognostic markers. Although increased SOC expression during PCa progression supports a role in cancer cell migration, the inverse association between TRPC1 and biochemical relapse suggests a protective effect in CLC. Moreover, the dramatic down-regulation of Orai1 in CRPC supports its role in apoptosis at this stage of the disease. These results call for caution when considering SOCs as potential therapeutic targets for PCa.