Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells

Bahar Salimian Rizi, Christine Caneba, Aleksandra Nowicka, Ahmad W. Nabiyar, Xinran Liu, Kevin Chen, Kevin M. Chen, Ann Klopp, Ann H. Klopp, Deepak Nagrath
Cancer research · 2014 · vol. 75(2) , pp. 456–471 · doi:10.1158/0008-5472.can-14-1337 · PMID:25425006 · W2128869557
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Omental adipose stromal cells increase nitric oxide levels in ovarian and endometrial cancer cells, promoting proliferation and chemoresistance via arginine-citrulline metabolic coupling.

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Abstract

Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that 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 propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic 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). Through arginine depletion in the media using l-arginase and NOS inhibition in cancer cells using N(G)-nitro-l-arginine methyl ester (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 use O-ASC-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, leading 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 using l-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers.

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MeSH descriptors

Adipose Tissue Cell Communication Endometrial Neoplasms Nitric Oxide Omentum Ovarian Neoplasms Stromal Cells Adipose Tissue Adipose Tissue Cell Communication Cell Line, Tumor Endometrial Neoplasms Endometrial Neoplasms Female Humans Nitric Oxide Omentum Omentum Ovarian Neoplasms Ovarian Neoplasms

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