Abstract 3916: HSP90 mediates tumor-associated matrix metalloproteinase 2 and Cathepsin L protease activities in ovarian carcinoma

Abstract

Abstract Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. At diagnosis, disease has commonly spread beyond the ovary. Ovarian cancer cells dislodge from primary tumor and spread locally throughout the abdominal cavity and lymphatics. Cancer cell shedding and colonization at other sites involves the degradation of extra cellular matrix (ECM) by tumor-associated proteases, such as matrix metalloproteinase (MMPs) and cathepsin proteases. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that interacts with and stabilizes MMPs in some solid tumors. Whether HSP90 regulates cathepsin activity is currently unknown. To determine the role of HSP90 on tumor-associated MMP and cathepsin protease activities in ovarian carcinoma, HSP90 activity was inhibited using pharmacologic and RNA interference (RNAi) approaches. A small molecule inhibitor, ganetespib, and two HSP90 targeting siRNAs were used to determine the effects of HSP90 inhibition on ovarian carcinoma cell line invasion using transwell and spheroid invasion assays. The effects of ganetespib or HSP90 targeting siRNA treatment on MMP and cathepsin protease activities were assayed by gelatin zymography (MMPs), enzyme assay (cathepsins) and by dynamic imaging using protease cleavable imaging probes. The effects of ganetespib treatment on in vivo orthotopic tumor growth, dissemination and tumor associated protease activities were determined using human ovarian carcinoma xenograft models. In vitro, ganetespib treatment or expression of HSP90-targeted siRNAs inhibited transwell and spheroid invasion, and MMP-2 and cathepsin L protease activities. In vivo, ganetespib treatment resulted in decreased growth of primary tumors and disseminated tumor nodules and decreased tumor-associated MMP and cathepsin activities. Importantly, significant inhibition of MMP and cathepsin activities was detected prior to differences in tumor volume, demonstrating rapid functional response to the drug. These results show that HSP90 regulates ovarian carcinoma-associated proteolytic activities that are essential to tumor progression and dissemination. They also point to the potential utility of HSP90 inhibition as a therapeutic strategy for the treatment of ovarian cancer. Citation Format: Shane W. O'Brien, Fang Xiao, Marsia A. Maglaty, Joshua S. Trinadad, Lainie P. Martin, David A. Proia, Denise C. Connolly. HSP90 mediates tumor-associated matrix metalloproteinase 2 and Cathepsin L protease activities in ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3916. doi:10.1158/1538-7445.AM2014-3916