Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells
Published version of a preprint
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 NG-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. Cancer Res; 75(2); 456–71. ©2014 AACR.
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The Warburg effect is the reliance of cancer cells on aerobic glycolysis even under normoxia.
“The Warburg effect, commonly observed characteristic of many cancer types, is identified as the reliance of cancer cells on aerobic glycolysis even under normoxia.”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Salimian Rizi et al., 2015
The Warburg effect leads to diversion of glucose to lactate, creating low pH conditions that modulate TME.
“This leads to diversion of glucose to lactate thereby creating low pH conditions which modulates TME (Warburg et al., 1927; Gatenby et al., 2006; Salimian Rizi et al., 2015).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Salimian Rizi et al., 2015
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- Authors
- Salimian Rizi, B., Caneba, C., Nowicka, A., Nabiyar, A. W., Liu, X., Chen, K., Klopp, A., & Nagrath, D.
- Affiliations
- 1Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas.
- Rice University (US)
- The University of Texas MD Anderson Cancer Center (US)
- 4GE Power & Water, Boulder, Colorado.
- Corresponding author
- Nagrath, Deepak
- Venue
- Cancer Research
- Published
- 2015-01-14
- Volume
- 75
- Issue
- 2
- Pages
- 456-471
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2128869557
- Cited by
- 98
- References
- 53
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 16 · 2023: 13 · 2022: 7 · 2021: 15 · 2020: 7 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 6 · 2015: 2
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- nitric oxide, mesenchymal stem cells, ovarian cancer, endometrial cancer, arginine metabolism, citrulline, nitric oxide synthase, L-NAME, tumor microenvironment, metabolic coupling, mitochondrial respiration, glycolysis, oxidative stress, chemoresistance, adipogenesis
- MeSH terms
- Adipose Tissue, Cell Communication, Female, Humans, Nitric Oxide, Omentum, Ovarian Neoplasms, Endometrial Neoplasms, Stromal Cells, Cell Line, Tumor
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