Abstract 2119: Regulation of T-type calcium channel expression during IL-6 induced neuroendocrine differentiation of prostate cancer cells

Abstract

Prostate cancer is the most common cancer among men. At early stages, the growth of prostate cancers is androgen dependent and therefore therapies designed to reduce the androgen concentration/receptor activation are effective in promoting tumor regression. At later stages, however, the growth of prostate cancers becomes androgen independent, leading to increased mortality. The switch to an androgen-refractory state is associated with neuroendocrine differentiation of prostate cancer cells. Several factors including interleukin-6 (IL-6) and increased cAMP production promote neuroendocrine differentiation of prostate cancer cells. How these factors promote neuroendocrine differentiation is not completely understood. In this work we investigated whether IL-6 evoked neuroendocrine differentiation of prostate cancer cells results in the stimulation of T-type calcium channel expression in the prostate cancer cell line LNCaP. Treatment of LNCaP cells with IL-6 for four days evokes considerable morphological and molecular changes consistent with neuroendocrine differentiation, including the presence of rounded cell bodies, the appearance of long dendritic-like processes and the expression of chromogranin-A. IL-6 evoked neuroendocrine differentiation of LNCaP cells results in a 3-fold increase in the protein expression of the T-type calcium channel subunit Cav3.2. Transcripts for the Cav3.2 but not Cav3.1 or Cav3.3 subunits can be detected in IL-6-treated LNCaP cells. Real time PCR analysis indicates no change in Cav3.2 mRNA expression between control (non-stimulated) and IL-6 stimulated LNCaP cells, suggesting that T-type calcium channel expression is regulated by a post-transcriptional mechanism. Electrophysiological recordings reveal that increased Cav3.2 protein expression following IL-6 stimulation of LNCaP cells does not result in increased expression of functional channels in the membrane. Functional expression of Cav3.2 channels is facilitated by stimulation of LNCaP cells with forskolin an agent that increases intracellular cAMP. These results indicate that changes in T-type calcium channel expression and intracellular calcium during neuroendocrine differentiation of LNCaP cells are regulated by the interplay of multiple factors. Thus, it appears that T-type calcium channels could be a target for future therapeutic strategies against prostate cancers refractory to anti-androgen therapies. Citation Format: Erika Weaver, Jennifer L. Hearne, Miguel Martin-Caraballo. Regulation of T-type calcium channel expression during IL-6 induced neuroendocrine differentiation of prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2119. doi:10.1158/1538-7445.AM2014-2119