T‐type calcium channels drive the proliferation of androgen‐receptor negative prostate cancer cells

Abstract

Background Androgen deprivation therapy (ADT) is the treatment of choice for metastatic prostate cancer (PCa). After an initial response to ADT, PCa cells can generate castration resistant (CRPC) or neuroendocrine (NEPC) malignancies, which are incurable. T‐type calcium channels (TTCCs) are emerging as promising therapeutic targets for several cancers, but their role in PCa progression has never been investigated. Methods To examine the role of TTCCs in PCa, we analyzed their expression level, copy number variants (CNV) and prognostic significance using clinical datasets (Oncomine and cBioPortal). We then evaluated TTCC expression in a panel of PCa cell lines and measured the effect of their inhibition on cell proliferation and survival using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and caspase assays. Results TTCCs were upregulated in PCas harboring androgen receptor (AR) mutations; CNV rate was positively associated with PCa progression. Higher expression of one TTCC isoform (CACNA1G) predicted poorer postoperative prognosis in early stage PCa samples. Pharmacological or small interfering RNA (siRNA)‐based inhibition of TTCCs caused a decrease in PC‐3 cell survival and proliferation. Conclusions Our results show that TTCCs are overexpressed in advanced forms of PCa and correlate with a poorer prognosis. TTCC inhibition reduces cell proliferation and survival, suggesting that there may be possible value in the therapeutic targeting of TTCCs in advanced PCa.

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

“…TTCCs have been shown to be involved in embryonic development and progression of several malignancies [142]. Recently, Silvestri et al, reported the overexpression of TTCCs isoform calcium voltage-gated channel subunit alpha1 G (CACNA1G) in advanced PCa that correlates with ADT resistance and poor prognosis while TTCC inhibition resulted in reduced PC3 cell proliferation and survival [143]. Previously, Gackiere and colleagues showed that another TTCC, CaV3.2 was highly expressed in NE cells derived from LNCaP cells.…”

Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms

“…Overexpression of voltage-operated calcium channel T-type calcium channels (TTCCs) has also been observed in PCa with androgen receptor mutations [59]. Moreover, it has been shown that pharmacological or silencing inhibition of TTCCs causes a decrease in PCa cell proliferation and survival [59]. Based on these observations, it has been proposed that TTCCs control the proliferation of androgen-receptor negative PCa cells [59].…”

“…Moreover, it has been shown that pharmacological or silencing inhibition of TTCCs causes a decrease in PCa cell proliferation and survival [59]. Based on these observations, it has been proposed that TTCCs control the proliferation of androgen-receptor negative PCa cells [59]. It has also been suggested that an androgen refractory state in which androgen receptor signaling is disrupted causes overexpression of TTCCs and increased cytosolic calcium in PCa cells [16].…”

Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer

“…Similarly, T-type calcium channels were revealed to be a promising target for different cancers, particularly PCa, in light of their role in tumor growth. SiRNA-based inhibition of these particular calcium channels was able to lessen PC-3 cell survival and proliferation [40]. Transient receptor potential melastatin 2 is another calcium-permeable ion channel and considered as a prognostic marker for PCa [41].…”

“…T-type calcium channels Lessens cell survival and proliferation of PC-3 cells. [40] Transient receptor potential melastatin 2 (TRPM2) Induces autophagy in PC-3 cells.…”