Androgen receptor signaling regulates T-type Ca2+ channel expression and neuroendocrine differentiation in prostate cancer cells

American Journal of Cancer Research

Megan Hall¹  Bryan Todd² 

[1] Department of Natural Sciences, School of Agricultural and Natural Sciences, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA;Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA

关键词: Prostate cancer;    bicalutamide;    neuroendocrine differentiation;    T-type calcium channel;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

Therapies designed to reduce androgen production or receptor activation are effective in limiting prostate tumor growth. However, prolonged treatment with anti-androgen therapies results in the progression of prostate cancers into an androgen refractory state. Neuroendocrine differentiation (NED) has been associated with the progression of prostate cancers to an androgen resistant phenotype. In this work we investigated the effect of disrupting androgen receptor signaling in promoting NED of prostate carcinoma cells and whether it is accompanied by an increase in T-type Ca2+ channel expression. The effect of disrupting androgen signaling was assessed in LNCaP and 22Rv1 prostate cancer cells following treatment with the androgen receptor blocker, bicalutamide, or hormone-depleted media. Treatment of LNCaP cells with bicalutamide or hormone-depleted media for 4-10 d evoked considerable morphological and biochemical changes consistent with NED including the development of long neurite-like processes and the expression of the neuronal marker, tubulin IIIβ. PCR analysis of bicalutamide-stimulated cells revealed no significant changes in Cav3.2 mRNA. However, stimulation of LNCaP cells with bicalutamide or hormone-depleted media for 10 d evoked a significant increase in Cav3.2 protein expression and the appearance of functional T-type Ca2+ channels. Inhibition of T-type Ca2+ channel function with various pharmacological blockers disrupted the morphological differentiation of LNCaP cells. Bicalutamide-evoked expression of functional T-type Ca2+ channels in LNCaP cells promoted chemoresistance to docetaxel. These findings indicate that disruption of androgen receptor signaling in prostate cancer cells evokes increased expression of functional T-type Ca2+ channels, which may result in significant morphological and biochemical changes.

【 授权许可】

CC BY-NC