Role Of Hsp90alpha-1, A Splice Variant Of Hsp90alpha, In Cancer

Molecular chaperone complexes, such as heat shock proteins 90 (Hsp90) and its co-chaperones, are essential for folding nascent polypeptides into their biologically active structures and for the refolding of aggregated and denatured proteins that occur upon cellular stress including cancer. Hsp90 exists as four isoforms in humans. Among them, Hsp90alpha is induced under stressful conditions, detected in the cytoplasm, nucleus and is secreted into extracellular space under metastatic conditions. Hsp90alpha is phosphorylated by DNA-PK at the nucleus under apoptotic conditions and localizes at the edge of the nucleus. Intrigued by the fact that Hsp90alpha might play a role in metastasis as well as in stress resistance, the mechanism of action of Hsp90alpha was investigated. Here we report that Hsp90alpha-1, a splice variant of Hsp90alpha, is up-regulated in cancer cells, predominantly associates with co-chaperone Aha1 in-vivo at the filopodia like extrusion of cell. The Hsp90alpha-1/Aha1 complex was partially disrupted by C- terminal inhibitors in-vivo conditions; and Hsp90alpha-1 and Aha1 redistributed to the cytoplasm from the filopodia following the treatment with the C- terminal inhibitors. Gene knock down analysis reveals that several P-Akt pathway and MAP Kinase pathway proteins were Hsp90alpha-1 dependent. P-Akt also co-localized with the Hsp90alpha-1/Aha1 complex at the filopodia region and suggests that Hsp90alpha-1 plays critical role in maturing/folding proteins that are important for establishing and maintaining cell polarity which is perturbed by the C- terminal inhibitors. Under apoptotic conditions the Hsp90alpha-1/Aha1 complex is present in the cytoplasm and nucleus and Hsp90alpha-1 is phosphorylated. Survivin, being a Hsp90alpha-1 dependent client protein, binds with the Hsp90alpha-1/Aha1 complex at normal and apoptotic conditions confirms that Survivin play dual role in mediating metastases as well as an Inhibitor of Apoptotic Protein (IAP). Citation Format: Suman Ghosh, Laura B. Peterson, George Vielhauer, Brian S. J Blagg. Role of Hsp90alpha-1, a splice variant of Hsp90alpha, in cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A16.