Nitric oxide and pH modulation in gynaecological cancer

Abstract

Nitric oxide plays several roles in cellular physiology, including control of the vascular tone and defence against pathogen infection. Neuronal, inducible and endothelial nitric oxide synthase (NOS) isoforms synthesize nitric oxide. Cells generate acid and base equivalents, whose physiological intracellular concentrations are kept due to membrane transport systems, including Na+/H+ exchangers and Na+/HCO 3 − transporters, thus maintaining a physiological pH at the intracellular (~7.0) and extracellular (~7.4) medium. In several pathologies, including cancer, cells are exposed to an extracellular acidic microenvironment, and the role for these membrane transport mechanisms in this phenomenon is likely. As altered NOS expression and activity is seen in cancer cells and because this gas promotes a glycolytic phenotype leading to extracellular acidosis in gynaecological cancer cells, a pro‐inflammatory microenvironment increasing inducible NOS expression in this cell type is feasible. However, whether abnormal control of intracellular and extracellular pH by cancer cells regards with their ability to synthesize or respond to nitric oxide is unknown. We, here, discuss a potential link between pH alterations, pH controlling membrane transport systems and NOS function. We propose a potential association between inducible NOS induction and Na+/H+ exchanger expression and activity in human ovary cancer. A potentiation between nitric oxide generation and the maintenance of a low extracellular pH (i.e. acidic) is proposed to establish a sequence of events in ovarian cancer cells, thus preserving a pro‐proliferative acidic tumour extracellular microenvironment. We suggest that pharmacological therapeutic targeting of Na+/H+ exchangers and inducible NOS may have benefits in human epithelial ovarian cancer.

Extracellular pH and lung infections in cystic fibrosis

“…Cells keep their acid-base regulation by using many metabolic enzymes, transporters and pH sensors. Their activities produce several acid-base equivalent species, including proton (H + ), lactate and carbon dioxide (CO 2 ) (Sanhueza et al, 2016), which are transported through plasma membrane (Seifter and Chang, 2017). The most important transporters that mediate pH homeostasis are ( Fig.…”

Induction of Secretagogue Independent Gastric Acid Secretion via a Novel Aspirin-Activated Pathway

“…When either the non-selective NOS inhibitor L-NAME ( N ω -Nitro-L-arginine methyl ester hydrochloride) or the specific sGC inhibitor ODQ was added, the aspirin-induced acid secretion was abolished. In fact, NO signaling is found to be an important pathway in many processes within the cells of the human body (Geller and Billiar, 1998; Sanhueza et al, 2016). Activation of the intracellular receptor NO-GC through NO increases the soluble guanylyl cyclase (sGC) and further to accumulation of cyclic guanosine monophosphate (cGMP) (Ignarro et al, 1987; Koesling et al, 2016; Kitay et al, 2017).…”

Activation of Secretagogue Independent Gastric Acid Secretion via Endothelial Nitric Oxide Synthase Stimulation in Rats

“…Evidence about a mitochondrial NOS have been reported, but scientists couldn´t identify structure and function to date [23, 24]. The endothelial nitric oxide synthase (eNOS) is responsible for the regulation of blood pressure and angiogenesis through intracellular signaling transductions [22, 25, 26] whereas the neuronal NOS (nNOS) is involved in neurotransmission, learning processes and synaptic plasticity [3, 25]. The isoforms eNOS and nNOS are acting via a calcium dependent pathway and regulate neuronal, and vascular processes through calmodulin binding [23].…”

“…The isoforms eNOS and nNOS are acting via a calcium dependent pathway and regulate neuronal, and vascular processes through calmodulin binding [23]. The third isoform of the NOS system, the inducible NOS (iNOS) plays an important role in innate immune responses and antipathogenic processes during infections with viruses and bacteria [25, 27, 28], and modulates tumor development [22, 25, 28]. The iNOS system is calcium-independent and produces high amounts of gas and radicals respectively, forming a cytotoxic microenvironment within the cell, which can be found during infection and tumor development [7].…”

“…Once L-arginine resides in the cell, the NOS converts it into NO and the byproduct L-citrulline [21]. Different types of NOS exist, which vary in distinct location and function: eNOS (NOS-3, endothelial), nNOS (NOS-1, neuronal) and iNOS (NOS-2, inducible) [22, 23]. Evidence about a mitochondrial NOS have been reported, but scientists couldn´t identify structure and function to date [23, 24].…”