Secreted Hsp90 Is a Novel Regulator of the Epithelial to Mesenchymal Transition (EMT) in Prostate Cancer

• Published in: The Journal of biological chemistry 2012-11, Vol.287 (45), p.37732-37744
• Main Authors: Hance, Michael W., Dole, Krystal, Gopal, Udhayakumar, Bohonowych, Jessica E., Jezierska-Drutel, Agnieszka, Neumann, Carola A., Liu, Haibo, Garraway, Isla P., Isaacs, Jennifer S.
• Format: Article
• Language: English
• Subjects: Antibodies, Blocking - immunology; Antibodies, Blocking - pharmacology; Blotting, Western; Cell Biology; Cell Line, Tumor; Cell Motility; Cell Movement - drug effects; Cell Movement - genetics; Dipeptides - pharmacology; Disease Progression; Epithelial to Mesenchymal Transition; Epithelial-Mesenchymal Transition - genetics; ERK; Extracellular Hsp90; Gene Expression Regulation, Neoplastic; HEK293 Cells; Hsp90; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - immunology; HSP90 Heat-Shock Proteins - metabolism; Humans; Low Density Lipoprotein Receptor-Related Protein-1 - genetics; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Male; Matrix Metalloproteinase (MMP); Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Prostate; Prostate Cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protease Inhibitors - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.389015

Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and the second highest contributor of male cancer related lethality. Disease mortality is due primarily to metastatic spread, highlighting the urgent need to identify factors involved in this progression. Activation of the genetic epithelial to mesenchymal transition (EMT) program is implicated as a major contributor of PCa progression. Initiation of EMT confers invasive and metastatic behavior in preclinical models and is correlated with poor clinical prognosis. Extracellular Hsp90 (eHsp90) promotes cell motility and invasion in cancer cells and metastasis in preclinical models, however, the mechanistic basis for its widespread tumorigenic function remains unclear. We have identified a novel and pivotal role for eHsp90 in driving EMT events in PCa. In support of this notion, more metastatic PCa lines exhibited increased eHsp90 expression relative to their lineage-related nonmetastatic counterparts. We demonstrate that eHsp90 promoted cell motility in an ERK and matrix metalloproteinase-2/9-dependent manner, and shifted cellular morphology toward a mesenchymal phenotype. Conversely, inhibition of eHsp90 attenuated pro-motility signaling, blocked PCa migration, and shifted cell morphology toward an epithelial phenotype. Last, we report that surface eHsp90 was found in primary PCa tumor specimens, and elevated eHsp90 expression was associated with increased levels of matrix metalloproteinase-2/9 transcripts. We conclude that eHsp90 serves as a driver of EMT events, providing a mechanistic basis for its ability to promote cancer progression and metastasis in preclinical models. Furthermore, its newly identified expression in PCa specimens, and potential regulation of pro-metastatic genes, supports a putative clinical role for eHsp90 in PCa progression. Background: Epithelial to mesenchymal transition (EMT) correlates with increased metastatic potential and poor prognosis. Results: Secreted eHsp90 induces EMT, matrix metalloproteinase activity and cell motility. Conclusion: EMT inducing activity of eHsp90 provides a mechanistic basis for its tumorigenic and metastatic function. Significance: The requirement for eHsp90 in supporting tumorigenic events indicates that targeting eHsp90 may represent a therapeutic approach to improve prostate cancer patient survival.