Abstract
Abstract Androgen receptor (AR), a member of the nuclear receptor superfamily, controls the growth regulatory and differentiation pathways in prostate epithelial cells, and its altered signaling is a pivotal event in the carcinogenesis of prostate epithelium. Previous studies show that basal Raf/MEK/extracellular signal-regulated kinase (ERK) activity is required for androgen-induced AR expression or for maintaining its levels in cells. However, loss of AR expression is correlated with upregulated Raf/MEK/ERK activity in certain contexts of PCa biology, including androgen withdrawal-induced PCa differentiation. Indeed, we found a strong correlation between AR downregulation and ERK1/2 phosphorylation in LNCaP cells cultured under a hormone-depleted condition and in the neuroendocrine derivates of LNCaP that were generated by prolonged culture under such condition. In this in vitro model, we investigated the role of Raf/MEK/ERK pathway in regulating AR expression. Sustained activation of the Raf/MEK/ERK pathway, mediated by an inducible Raf, was sufficient to induce AR downregulation at mRNA and protein levels in LNCaP. Interestingly, when the intensity of Raf induction was serially decreased to levels under a certain threshold, activation of the Raf/MEK/ERK pathway no longer downregulated but rather upregulated AR levels in cells. Our study therefore suggests that the Raf/MEK/ERK pathway can regulate AR levels in PCa cells in opposing contexts depending upon its different signaling intensity. We also found that sustained Raf/MEK/ERK activation can induce downregulation of full length AR as well as hormone binding domain-deficient AR isoforms in CWR22Rv1 cells, which are known to more potently stimulate PCa cell growth. Further investigation of the mechanisms underlying Raf/MEK/ERK-mediated AR downregulation may lead to a novel means to control AR levels in PCa cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2011-1938
Published Version
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