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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DE020203-03
Application #
8197834
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2009-12-01
Project End
2013-05-31
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$48,032
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Qin, Zhiqiang; Dai, Lu; Defee, Michael et al. (2013) Kaposi's sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection. J Virol 87:621-35
Dai, Lu; Qin, Zhiqiang; Defee, Michael et al. (2012) Kaposi sarcoma-associated herpesvirus (KSHV) induces a functional tumor-associated phenotype for oral fibroblasts. Cancer Lett 318:214-20
Renne, Walter; McGill, Samuel T; Forshee, Kaitlyn VanSickle et al. (2012) Predicting marginal fit of CAD/CAM crowns based on the presence or absence of common preparation errors. J Prosthet Dent 108:310-5
Defee, Michael R; Qin, Zhiqiang; Dai, Lu et al. (2011) Extracellular Hsp90 serves as a co-factor for NF-?B activation and cellular pathogenesis induced by an oncogenic herpesvirus. Am J Cancer Res 1:687-700
Defee, Michael R; Qin, Zhiqiang; Dai, Lu et al. (2011) Interactions between Hsp90 and oncogenic viruses: implications for viral cancer therapeutics. Am J Cancer Res 1:763-72
Qin, Zhiqiang; DeFee, Michael; Isaacs, Jennifer S et al. (2010) Extracellular Hsp90 serves as a co-factor for MAPK activation and latent viral gene expression during de novo infection by KSHV. Virology 403:92-102