CaV3.2 T-type Calcium Channels Are Involved in Calcium-dependent Secretion of Neuroendocrine Prostate Cancer Cells

Abstract

Because prostate cancer is, in its early stages, an androgen-dependent pathology, treatments aiming at decreasing testosterone plasma concentration have been developed for many years now. However, a significant proportion of patients suffer a relapse after a few years of hormone therapy. The androgenindependent stage of prostate cancer has been shown to be associated with the development of neuroendocrine differentiation. We previously demonstrated that neuroendocrine prostate cancer cells derived from LNCaP cells overexpress CaV3.2 T-type voltage-dependent calcium channels. We demonstrate here using prostatic acid phosphatase as a marker of prostate secretion and FM1-43 fluorescence imaging of membrane trafficking that neuroendocrine differentiation is associated with an increase in calcium-dependent secretion which critically relies on CaV3.2 T-type calcium channel activity. In addition, we show that these channels are expressed by neuroendocrine cells in prostate cancer tissues obtained from patients after surgery. We propose that CaV3.2 T-type calcium channel up-regulation may account for the alteration of secretion during prostate cancer development and that these channels, by promoting the secretion of potential mitogenic factors, could participate in the progression of the disease toward an androgen-independent stage.Prostate cancer is, in its early stages, an androgen-dependent pathology, meaning that its progression relies on the presence of active steroid male hormones. Treatments developed for many years have been based on this characteristic feature of prostate cancer and, thus, aimed at decreasing the plasma concentration of testosterone or dihydrotestosterone, the prostate active androgen. Although these treatments are particularly valuable in the early development of the disease, leading to the regression of cancers, about a third of the patients suffer a relapse after a few years of hormone therapy. At this stage of hormone refractory disease, deprivation of androgens has no further incidence on the growth of the prostate cancer, and no curative therapy is currently effective (for review, see Ref. 1).The androgen-independent stage of prostate cancer has been shown to be associated with, among others, the development of neuroendocrine differentiation (2). These neuroendocrine features include the appearance of neuroendocrine cell foci surrounded by proliferating epithelial cells (3). Because neuroendocrine prostate cells in normal, hyperplastic, or cancerous tissue secrete many neuropeptides with mitogenic activities like parathyroid hormone-related peptide, calcitonin, or gastrin-related peptides, it has been proposed that paracrine secretion of neurosecretory products released by neuroendocrine cells could be responsible for the progression of cancer toward an androgen-independent stage (for review, see Ref. 4). Indeed, it has been shown for instance that the expression of neuroendocrine markers like chromogranin A is correlated with tumor dedifferentiation (5) and that the presence of neuroendo...

Expression and Role of T-type Calcium Channels during Neuroendocrine Differentiation

“…Indeed, PAP expression is increased in prostate bone metastasis and PAP may participate in the osteoblastic phase of the metastasis development [115]. Moreover, we have shown that the expression of Cav3.2 channels is correlated with the expression of serotonin [86], a neurotransmitter stimulating the proliferation and migration of prostate cancer cell lines [116]. Furthermore, we have shown that Cav3.2 expression correlates with CgA expression [86].…”

“…Their role in cell proliferation may be due to the fact that enhanced expression of T-type calcium channels (Cav3.1, Cav3.2 or Cav3.3) leads to increased secretion of tumorigenic factors by NE cells. As we have previously shown, PAP synthesis and release are enhanced by Cav3.2 channels in LNCaP cells [86]. In addition, the secreted form of PAP may play an important role in the development of prostate tumour metastasis.…”

“…Moreover, we have shown that the expression of Cav3.2 channels is correlated with the expression of serotonin [86], a neurotransmitter stimulating the proliferation and migration of prostate cancer cell lines [116]. Furthermore, we have shown that Cav3.2 expression correlates with CgA expression [86]. The circulating level of CgA, an NE marker, is frequently increased in the advanced stages of the diseases.…”

“…Furthermore, PAP secretion is reduced by low concentrations of NiCl 2 , flunarizine or kurtoxin and by siRNAs targeting Cav3.2 channels. Cav3.2 expression and activity are therefore responsible for PAP secretion in NE prostate cancer cells [86]. In addition, it has been demonstrated that Cav3.2 channels are activated by hydrogen sulfide (H 2 S) which is produced by an overexpression of cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) during NE differentiation of LNCaP cells [73].…”

A Novel Alternative for Cancer Therapy: Pharmacological Modulation of Ca2+/cAMP Intracellular Signaling Interaction

“…Novel splice variants of T-type VACC are commonly detected in human glioma, breast, ovarian, prostate colon and esophageal cancer cells [36][37][38][39][40] . For example, the Cav3.1a transcripts predominate in the normal adult brain, but human glioma and glioma cell lines contain Cav3.1bc as predominant splice and Cav3.1ac as a novel splice variant, which is absent in normal brain [36][37][38][39][40] . 45 .…”