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.

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

“…0.8 increased NADPH and reduced ROS in cocultures under argininedeprivation conditions. These results substantiate the role of O-ASC-secreted factors that modulate NO homeostasis in cancer cells and thereby upregulate glycolysis and reduce oxidative stress (30).…”

Benzo[a]pyrene-induced nitric oxide production acts as a survival signal targeting mitochondrial membrane potential

“…It is worth noting that mitochondrial hyperpolarization has been related to alterations of the oxidative phosphorylation, evidenced by a decrease in cell respiration (Forkink et al, 2014), with concomitant stimulation of glycolysis in order to maintain ATP production (Sánchez-Cenizo et al, 2010). A similar link between reduced mitochondrial activity and shift toward glycolysis due to NO has been previously reported, for example in ovarian cancer cells (Caneba et al, 2014;Chang et al, 2015). The involvement of such a metabolic reprogramming upon B[a]P is currently under investigation and should allow unraveling the mechanisms underlying the NO brake effect toward B[a]P-induced apoptosis.…”

iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer

“…It has been reported that nitric oxide promotes glycolysis in ovary cancer cells, but the mechanism was unknown [11]. In this study, we elucidated the dual effects of exogenous nitric oxide on glycolytic regulation: at low concentration, nitric oxide promotes glycolysis and inhibits at high concentration.…”