S3-2 Roles of the hydrogen sulfide-CAV3.2 T-type calcium channel pathway in neuronal and neuroendocrine differentiation

Abstract

H2S, a gasotransmitter, is formed by multiple enzymes including cystathionine-gamma-lyase (CSE). H2S enhances function of Cav3.2 T-type calcium channels in NG108-15 cells, isolated dorsal root ganglion neurons and Cav3.2-transfected HEK293 cells, and the H2S/Cav3.2 pathway plays a role in somatic and visceral pain signaling. H2S also causes Cav3.2-dependent neuronal differentiation characterized by neuritogenesis in NG108-15 cells. Interestingly, androgen-sensitive human prostate cancer LNCaP cells exhibit neuroendocrine-like differentiation following elevation of intracellular cyclic AMP levels or androgen deprivation, and the differentiated cells abundantly express Cav3.2 responsible for calcium-dependent secretion of proliferation factors. We have found that neuroendocrine-like differentiation causes upregulation of CSE as well as Cav3.2, and endogenous H2S formed by CSE facilitates Cav3.2 function and then secretory responses in LNCaP cells. Expression of Egr1 at an early stage appears to be involved in transcriptional upregulation of Cav3.2. Our study thus suggest that H2S formed by upregulated CSE regulates secretory function via activation of upregulated Cav3.2 in neuroendocrine-like differentiated LNCaP cells, contributing to androgen-independent proliferation of surrounding cells, and the CSE/H2S/Cav3.2 pathway might serve as targets for pharmacological interventions for preventing acquisition of hormone therapy resistance of prostate cancer.