Abstract 1882: Role of cystathionine beta-synthase in ovarian cancer growth, metastasis and drug sensitivity.

Abstract

Abstract Hydrogen sulfide (H2S), the third gasotransmitter, has recently attracted a lot of attention for its cytoprotective action and role in angiogenesis. Dysregulation of the major enzymes which produces H2S namely, cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) have also been implicated in a large number of pathological conditions that range from neurological disorders to cardiovascular diseases. Surprisingly, studies on the role of these enzymes in cancer is scarce, especially, that of CBS. Relapse with a drug resistant and aggressive phenotype is a common occurrence in ovarian cancer with an overall 5-year survival of approximately 30%. Here we report that, CBS, a key enzyme required for sulphur amino acid metabolism, plays a critical role in promoting ovarian cancer growth, metastasis and drug resistance. Overexpression of CBS was observed in a majority of ovarian cancer cell lines utilized in our study compared to normal ovarian surface epithelial cells. Silencing CBS in A2780 cells using siRNA or a CBS-specific inhibitor, aminooxyacetic acid reduced proliferation of ovarian cancer cells by dramatically reducing total glutathione levels, H2S levels and thereby enhancing oxidative stress. Downregulation of CBS reduced activation of NF-kB and upregulated p53 protein levels thereby inactivating the antioxidant network of the cells. A deeper insight into the intracellular localization of CBS by confocal fluorescence microscopy demonstrated a mitochondria specific distribution and silencing CBS caused mitochondrial superoxide accumulation that resulted in decreased mitochondrial respiration, reduced ATP production and increased ADP-to-ATP ratio. Furthermore, silencing CBS, augmented the activity of cisplatin in vitro in A2780 cells and in vivo in an orthotopic model of advanced ovarian cancer. Nanoliposomal delivery of CBS siRNA significantly reduced the number of tumor nodules in a chemoresistant orthotopic mouse model of ovarian cancer. To our knowledge, this is the first study demonstrating the importance of CBS in ovarian cancer progression and drug resistance and therefore is a viable target for future anti-cancer therapies. Citation Format: Sounik Saha, Sanjib Bhattacharyya, Karuna Giri, Ian R. Lanza, K. Sreekumar Nair, Nicholas B. Jennings, Rakesh Kumar, Anil K. Sood, Resham Bhattacharya, Priyabrata Mukherjee. Role of cystathionine beta-synthase in ovarian cancer growth, metastasis and drug sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2013-1882