Abstract 348: Extracellular heat shock protein 90 (eHsp90) initiates EMT events and enhances cell motility in prostate cancer

Abstract

Abstract Prostate Cancer (PCa) is the most commonly diagnosed malignancy in men, responsible for the second highest lethality. Although early cancer detection and treatment is often curative, subsequent metastatic spread of tumor cells renders the disease incurable. Activation of the epithelial to mesenchymal transition (EMT) genetic program is considered a key event contributing to metastatic potential and subsequent lethality. Although targeting EMT may be a promising approach for improving treatment outcome, the main, potentially druggable, targets driving this pathway in PCa remain poorly defined. Multiple reports indicate that extracellular Hsp90 (eHsp90) promotes cell motility, invasion, and metastasis in a number of cancer cell types. Intriguingly, eHsp90 has been preferentially detected in the serum or plasma from aggressive cancers. Its presence in the serum of metastatic PCa patients implicates a potential causative role in PCa. Therefore, our objective was to investigate whether eHsp90 may influence EMT events, thereby influencing the metastatic potential of PCa. We now report that paired sets of differentially aggressive PCa tumor cell lines exhibited higher expression of eHsp90. Functionally, exposure of PCa cells to eHsp90 elicted a significant increase in cell motility. Inversely, blockade of eHsp90 attenuated the activation of several pro-motility effectors, concomitant with the significant suppression of cell migration. These events were associated with a profound alteration of cellular morphology towards a mesenchymal phenotype. Changes in cell phenotype were coupled with a loss and redistribution of the EMT suppressive gatekeeper protein E-cadherin. eHsp90 was also found to impact on the localization of other junctional proteins known to maintain a cuboidal epithelial phenotype. Finally, eHsp90 was found to transcriptionally upregulate several of the established transcriptional factors known to initiate EMT events. Confirmation of the EMT inducing ability of eHsp90 was determined by focused quantitative real time EMT PCR arrays. Our results therefore highlight a novel role for eHsp90 as a central regulator of EMT events in PCa. Our findings further support the premise that therapeutic targeting of eHsp90 may have the potential to suppress EMT activation and diminish the dissemination and metastatic propensity of PCa tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 348. doi:1538-7445.AM2012-348