Role of low voltage-activated Ca_v3.2 T-type Ca²⁺ channels in prostate cancer cells

Abstract

Ca_v3.2 T-type Ca²⁺ channels regulate neuronal excitability, contributing to pain signaling, and their function is enhanced by H₂S, a gasotransmitter. Ca_v3.2 is also expressed in certain cancer cells, and may affect cancer patients' prognosis. We have been studying the role of Ca_v3.2 in human prostate cancer LNCaP cells, particularly during neuroendocrine (NE)-like differentiation, which might be involved in hormone therapy resistance of prostate cancer. Ca_v3.2 and cystathionine γ-lyase (CSE), an H₂S-generating enzyme, are overexpressed in LNCaP cells during NE differentiation, accompanied by upregulation of Egr-1 and downregulation of REST, which contribute to transcriptional upregulation of Ca_v3.2. These events may participate in increased secretion of mitogenic factors essential for proliferation of surrounding cells. Further, increased extracellular glucose levels accelerate functional upregulation and overexpression of Ca_v3.2 probably through asparagine-linked glycosylation of Ca_v3.2. Our study thus suggests a crucial role of the H₂S/Ca_v3.2 system in NE-like differentiated LNCaP cells, which is promoted by hyperglycemia, being consistent with the clinical evidence that diabetes is a risk factor for castration-resistance of prostate cancer.