Abstract 2995: Loss of SHISA3 is an early event of the epithelial-to-mesenchymal transition associated with chemoresistance in prostate cancer

Abstract

Abstract Background: Despite scientific advances over the past decade, prostate cancer still remains the fifth leading cause of death from cancer in men worldwide. Docetaxel has an established role in the treatment of metastatic castrate-resistant prostate cancer (CRPC). However, malignant cells frequently acquire Docetaxel resistance. Therefore, further research is required to understand the molecular mechanisms underlying Docetaxel-resistance, which could be helpful in formulating alternative and superior therapeutic strategies. Methods: Two Docetaxel-resistant prostate cancer cell lines (IGR-CaP1 and PC3) were obtained by continuous exposure to Docetaxel. By comparing genes and miRs expression profiles established in these two Docetaxel-resistant models, we observed an enrichment of genes involved in the epithelial-to-mesenchymal transition (EMT) in the chemoresistant models and identified new genes potentially implicated in the resistance mechanism. Results: We identified the SHISA3 gene as a highly down-regulated gene in resistant cells. This gene was originally identified as an inhibitor of Wnt and FGF signaling during development in Xenopus. We showed that SHISA3 was lost during the acquisition of resistance to Docetaxel possibly via an EMT mechanism. Knockdown of SHISA3 in the parental IGR-CaP1 and PC3 cells triggered loss of the tight junction protein Occludin, engaged the Cadherin switch and increased the migratory properties of cells in vitro. Loss of SHISA3, along with loss of E-cadherin expression and expression of the mesenchymal marker N-cadherin were also observed in Docetaxel-resistant tumors obtained from IGR-CaP1-R xenografted mice. Phylogenetic comparison of SHISA3 gene sequences suggested that it may correspond to transmembrane adapters capable of regulating the activity of membrane receptors such as growth factor receptors. We are currently studying the binding partners of SHISA3 in our models by a proteomic approach to identify the implicated signaling pathway in prostate cancer. Conclusion: Our results show that loss of SHISA3 is an early event linked to the EMT process associated with chemoresistance and suggest that SHISA3 could be a useful biomarker to identify chemoresistant cells. Moreover, identification of its mechanism of action may lead to the identification of new therapeutic targets to overcome Docetaxel resistance. Citation Format: Nicolas J-p Martin, Sophie Cotteret, Catherine Gaudin, Marine Garrido, Safae Aarab-Terrisse, Nader al Nakouzi, Lucas Gentilini, Daniel Compagno, Vasily Ogryzko, Guillaume Meurice, Karim Fizazi, Anne Chauchereau. Loss of SHISA3 is an early event of the epithelial-to-mesenchymal transition associated with chemoresistance in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2995. doi:10.1158/1538-7445.AM2015-2995