Kaposi sarcoma (KS) is the most common cancer arising in HIV- infected individuals with as many as 60% of cases involving the oral cavity. Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of KS, activates signal transduction pathways responsible for promoting viral oncogene expression, cell migration and other events important for KS pathogenesis. Heat shock protein 90 (HSP90) plays an important role in cancer pathogenesis as well as the life cycle for certain viruses. We have established that HSP90 associated with the cell surface facilitates KSHV gene expression during de novo infection, in part through the activation of mitogen activated protein kinase (MAPk) pathways. We have also found that Hsp90 facilitates KSHV activation of nuclear factor kappa B (NF-kB) during de novo infection independent of MAPk activation. Finally, we found that KSHV-induced secretion of pro-angiogenic soluble factors like IL-8 and VEGF is regulated by HSP90. Given these data, we hypothesize that HSP90 facilitates KSHV-induced cell migration by acting as a co-factor in the induction of pro-angiogenic signal transduction by KSHV. We will test this hypothesis through the completion of the following specific aims: 1. To determine the signal transduction pathways through which HSP90 facilitates KSHV-induced secretion of pro-angiogenic factors. Using western blot and gene transfer, we will characterize the intracellular signaling events through which Hsp90 mediates KSHV-induced release of MMP-9, IL-8 and VEGF with an initial focus on MAPK, NF-kB, and FAK pathways. 2. To determine the effect of HSP90 inhibition on KSHV cell migration and invasion. Using well-established assays for cell migration/invasion, we will characterize the effect of HSP90 inhibition on KSHV-mediated migration of endothelial cells, and fibroblasts. Public Health Relevance: The CDC estimates that there are over 1 million people infected with HIV in the United States. Improving the oral health of HIV-infected individuals is a critical mission of the NIDCR, and our research explores novel mechanisms and related therapeutic strategies for the most common oral cancer aflicting these patients. Furthermore, currently available therapies for KS incur significant side effects that are with limited therapeutic benefit.
