title: Nitric oxide is a positive regulator of the Warburg effect in ovarian cancer cells.
abstract: Ovarian cancer (OVCA) is among the most lethal gynecological cancers leading to high mortality rates among women. Increasing evidence indicate that cancer cells undergo metabolic transformation during tumorigenesis and growth through nutrients and growth factors available in tumor microenvironment. This altered metabolic rewiring further enhances tumor progression. Recent studies have begun to unravel the role of amino acids in the tumor microenvironment on the proliferation of cancer cells. One critically important, yet often overlooked, component to tumor growth is the metabolic reprogramming of nitric oxide (NO) pathways in cancer cells. Multiple lines of evidence support the link between NO and tumor growth in some cancers, including pancreas, breast and ovarian. However, the multifaceted role of NO in the metabolism of OVCA is unclear and direct demonstration of NO's role in modulating OVCA cells' metabolism is lacking. This study aims at indentifying the mechanistic links between NO and OVCA metabolism. We uncover a role of NO in modulating OVCA metabolism: NO positively regulates the Warburg effect, which postulates increased glycolysis along with reduced mitochondrial activity under aerobic conditions in cancer cells. Through both NO synthesis inhibition (using L-arginine deprivation, arginine is a substrate for NO synthase (NOS), which catalyzes NO synthesis; using L-Name, a NOS inhibitor) and NO donor (using DETA-NONOate) analysis, we show that NO not only positively regulates tumor growth but also inhibits mitochondrial respiration in OVCA cells, shifting these cells towards glycolysis to maintain their ATP production. Additionally, NO led to an increase in TCA cycle flux and glutaminolysis, suggesting that NO decreases ROS levels by increasing NADPH and glutathione levels. Our results place NO as a central player in the metabolism of OVCA cells. Understanding the effects of NO on cancer cell metabolism can lead to the development of NO targeting drugs for OVCAs.
authors: 1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Bioengineering, Rice University, Houston, TX, USA.
authors: C A
authors: CA
authors: Caneba
authors: 1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors: L
authors: L
authors: Yang
authors: 1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors: J
authors: J
authors: Baddour
authors: 1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors: R
authors: R
authors: Curtis
authors: 1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors: J
authors: J
authors: Win
authors: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors: S
authors: S
authors: Hartig
authors: 1] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [2] Pediatric Critical Care Medicine and USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors: J
authors: J
authors: Marini
authors: 1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Bioengineering, Rice University, Houston, TX, USA [3] Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors: D
authors: D
authors: Nagrath
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009249:NADP / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D009249:NADP; D005978:Glutathione