Abstract 2912: Nitric oxide mediates metabolic coupling of omentum-derived adipose to ovarian and endometrial cancer cells
Authors: Salimian Rizi Bahar , Chen Kevin , Didelija Inka Cajo , Marini Juan , Klopp Ann H. , Nagrath Deepak 
Published: August 2015

Abstract
Omental adipose stromal cells (O-ASCs) are multipotent population of mesenchymal stem cells contained in the omentum tissue which promote endometrial and ovarian tumor proliferation, migration and drug resistance. The mechanistic underpinnings of O-ASCs role in tumor progression and growth are unclear. Here, we report a novel nitric oxide (NO) mediated metabolic coupling between O-ASCs and gynecological cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Ovarian cancers have high affinity for NO which has solubility in lipids. This explains the proximity of many carcinomas to fatty tissue, and thus the high positive correlation between obesity and cancer. Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using L-NAME, we demonstrate that patient derived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells utilize O-ASCs-secreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells which led to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASC mediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment secreted factors induced increased NO synthesis in cancer cells using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Interestingly, we found that NO modulates s-nitrosation of cellular proteins mediating energy metabolism and cellular differentiation. O-ASCs were found to synthesize higher levels of NO during their differentiation to fat cells which leads to higher protein s-nitrosation. Inhibition of s-nitrosation of cellular proteins showed that NO-mediated protein modifications are strongly associated with O-ASCs adipogenesis. In summary, our data indicate that modulation of intrinsic NO substantially affects tumor growth and drug toxicity in ovarian and endometrial cancer cells. Our study will lead to significant advances in the understanding of the omentum in altering cancer metabolism and lead to novel therapeutics.
Citation Format: Bahar Salimian Rizi, Kevin Chen, Inka Cajo Didelija, Juan Marini, Ann H. Klopp, Deepak Nagrath. Nitric oxide mediates metabolic coupling of omentum-derived adipose to ovarian and endometrial cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2912. doi:10.1158/1538-7445.AM2015-2912