Sekiguchi Fumiko, Kawabata Atsufumi
Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University.
Nihon Yakurigaku Zasshi. 2019;154(3):97-102. doi: 10.1254/fpj.154.97.
Among voltage-gated Ca channels, T-type Ca 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 Ca channels, Ca3.2 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 Ca3.2 in human prostate cancer LNCaP cells during NE-like differentiation. NE-like LNCaP cells overexpress Ca3.2 through the CREB/Egr-1 pathway and also cystathionine-γ-lyase (CSE), which generates HS that enhances the channel activity of Ca3.2. HS generated by upregulated CSE appears to enhance the activity of upregulated Ca3.2 after the differentiation. The enhanced Ca3.2 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 Ca3.2 activity through asparagine (N)-linked glycosylation of Ca3.2, which might contribute to diabetic neuropathy. We then found that high glucose accelerates the enhanced channel function and overexpression of Ca3.2 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, Ca3.2 is considered to play a role in the pathophysiology of prostate cancer, and may serve as a therapeutic target.
在电压门控钙通道中，T型钙通道可被低电压激活，调节神经元兴奋性、神经递质的自发释放、激素分泌等，还参与不同癌细胞的增殖。在T型钙通道的三种亚型中，Ca3.2在100%的前列腺癌患者活检样本中均可检测到。一般来说，前列腺癌细胞对雄激素剥夺疗法高度敏感，但常常会产生激素治疗抵抗。雄激素剥夺可能会触发一些前列腺癌细胞的神经内分泌（NE）样分化。我们分析了人前列腺癌LNCaP细胞在NE样分化过程中Ca3.2的表达和功能。NE样LNCaP细胞通过CREB/Egr-1途径过表达Ca3.2，还过表达胱硫醚-γ-裂解酶（CSE），CSE可生成硫化氢（HS），增强Ca3.2的通道活性。分化后，上调的CSE产生的HS似乎增强了上调的Ca3.2的活性。NE样细胞中增强的Ca3.2活性可能有助于增加对周围前列腺癌细胞雄激素非依赖性增殖至关重要的促有丝分裂因子的分泌。已知细胞外葡萄糖水平升高通过Ca3.2的天冬酰胺（N）-连接糖基化增强Ca3.2活性，这可能导致糖尿病性神经病变。然后我们发现高糖加速了NE样LNCaP细胞中Ca3.2通道功能的增强和过表达，这可能与糖尿病相关的前列腺癌预后不良和激素治疗抵抗发展的临床证据有关。因此，Ca3.2被认为在前列腺癌的病理生理学中起作用，并可能成为一个治疗靶点。
