Abstract 3415: Diverse roles for Snail transcription factor in epithelial-mesenchymal transition (EMT) and neuroendocrine differentiation (NED) in human prostate cancer

Abstract

Abstract Snail transcription factor induces epithelial-mesenchymal transition (EMT) via decreased cell adhesion-associated molecules like E-cadherin, and increased mesenchymal markers like vimentin. We previously established Snail-mediated EMT model utilizing androgen-dependent LNCaP cells. These cells express increased vimentin protein and relocalization of E-cadherin from the cell membrane to the cytosol. Interestingly, Snail transfection in LNCaP cells resulted in cells acquiring a neuroendocrine-like morphology with long neurite-like processes. We tested for expression of neuroendocrine markers neuron specific enolase (NSE) and chromogranin A (CgA) by Western blot analysis, and performed proliferation assays to test for paracrine cell proliferation. LNCaP cells transfected with Snail displayed increase in the neuroendocrine markers, NSE and CgA as well as translocation of androgen receptor to the nucleus. We found that LNCaP C-33 cells that have been previously published as a Neuroendocrine Differentiation (NED) model exhibited increased expression levels of Snail protein as compared to LNCaP parental cells. Functionally, conditioned medium from the LNCaP-Snail transfected cells increased proliferation of parental LNCaP and PC-3 cells. In addition, NED in LNCaP-C33 cells or that induced in parental LNCaP cells by serum starvation could be inhibited by knockdown of Snail with siRNA. Knockdown of NSE and CgA with siRNA abrogated Snail induced paracrine cell proliferation in parental LNCaP and PC3 cells. Immunohistochemical staining of prostate cancer patient tissue revealed increased expression of Snail with prostate cancer progression and bone metastasis. Higher Snail staining was observed in primary prostate cancer tissue containing a neuroendocrine component (identified by CgA staining) as compared to primary cancer with no neuroendocrine differentiation. However, in metastatic tissue, Snail was highly expressed in both neuroendocrine and non-neuroendocrine cancer tissue. Overall our data provide evidence that Snail transcription factor may promote tumor aggressiveness in the prostate cancer cells through multiple processes; induction of EMT may be required to promote migration, while NED may promote tumor proliferation by a paracrine mechanism. Therefore, therapeutic targeting of Snail may prove beneficial in not only abrogating EMT but also NED. 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 3415. doi:10.1158/1538-7445.AM2011-3415