[Role of Ca_v3.2 T-type Ca²⁺ channels in prostate cancer cells].

Among voltage-gated Ca²⁺ channels, T-type Ca²⁺ channels, which are activated by low voltages, regulate neuronal excitability, spontaneous neurotransmitter release, hormone secretion, etc. and also participate in proliferation of distinct cancer cells. Among three isoforms of T-type Ca²⁺ channels, Ca_v3.2 is detectable in 100% of biopsy samples from prostate cancer patients. In general, prostate cancer cells are highly sensitive to androgen deprivation therapy, but often acquire hormone-therapy resistance. The androgen deprivation may trigger neuroendocrine (NE)-like differentiation of some prostate cancer cells. We have analyzed the expression and function of Ca_v3.2 in human prostate cancer LNCaP cells during NE-like differentiation. NE-like LNCaP cells overexpress Ca_v3.2 through the CREB/Egr-1 pathway and also cystathionine-γ-lyase (CSE), which generates H₂S that enhances the channel activity of Ca_v3.2. H₂S generated by upregulated CSE appears to enhance the activity of upregulated Ca_v3.2 after the differentiation. The enhanced Ca_v3.2 activity in NE-like cells may contribute to increased secretion of mitogenic factors essential for androgen-independent proliferation of surrounding prostate cancer cells. It is known that increased extracellular glucose levels enhance Ca_v3.2 activity through asparagine (N)-linked glycosylation of Ca_v3.2, which might contribute to diabetic neuropathy. We then found that high glucose accelerates the enhanced channel function and overexpression of Ca_v3.2 in NE-like LNCaP cells, which might be associated with clinical evidence for diabetes-related poor prognosis of prostate cancer and development of hormone therapy resistance. Thus, Ca_v3.2 is considered to play a role in the pathophysiology of prostate cancer, and may serve as a therapeutic target.

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