Store-operated Ca 2+ channels in prostate cancer epithelial cells: function, regulation, and role in carcinogenesis

Abstract

Ca 2+ homeostasis mechanisms, in which the Ca 2+ entry pathways play a key role, are critically involved in both normal function and cancerous transformation of prostate epithelial cells. Here, using the lymph node carcinoma of the prostate (LNCaP) cell line as a major experimental model, we characterize prostate-specific store-operated Ca 2+ channels (SOCs)—a primary Ca 2+ entry pathway for non-excitable cells—for the first time. We show that prostate-specific SOCs share major store-dependent, kinetic, permeation, inwardly rectifying, and pharmacological (including dual, potentiation/inhibition concentration-dependent sensitivity to 2-APB) properties with “classical” Ca 2+ release-activated Ca 2+ channels (CRAC), but have a higher single channel conductance (3.2 and 12 pS in Ca 2+- and Na +-permeable modes, respectively). They are subject to feedback inhibition via Ca 2+-dependent PKC, CaMK-II and CaM regulatory pathways and are functionally dependent on caveolae integrity. Caveolae also provide a scaffold for spatial co-localization of SOCs with volume-regulated anion channels (VRAC) and their Ca 2+-mediated interaction. The TRPC1 and TRPV6 members of the transient receptor potential (TRP) channel family are the most likely molecular candidates for the formation of prostate-specific endogenous SOCs. Differentiation of LNCaP cells to an androgen-insensitive, apoptotic-resistant neuroendocrine phenotype downregulates SOC current. We conclude that prostate-specific SOCs are important determinants in the transition to androgen-independent prostate cancer.