Cancer cell metabolism and the modulating effects of nitric oxide

Abstract

Altered metabolic phenotype has been recognized as a hallmark of tumor cells for many years, but this aspect of the cancer phenotype has come into greater focus in recent years. NOS2 (inducible nitric oxide synthase of iNOS) has been implicated as a component in many aggressive tumor phenotypes, including melanoma, glioblastoma and breast cancer. Nitric oxide has been well established as a modulator of cellular bioenergetics pathways, in many ways similar to the alteration of cellular metabolism observed in aggressive tumors. In this review we attempt to bring these concepts together with the general hypothesis that one function of NOS2 and NO in cancer is to modulate metabolic processes to facilitate increased tumor aggression. There are many mechanisms by which NO can modulate tumor metabolism, including direct inhibition of respiration, alterations in mitochondrial mass, oxidative inhibition of bioenergetic enzymes, and the stimulation of secondary signaling pathways. Here we review metabolic alterations in the context of cancer cells and discuss the role of NO as a potential mediator of these changes.

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.…”

Role of ESR Pathway Genes in Breast Cancer: A Review

“…It would be therefore interesting to examine the association of these proteins during breast cancer development. Furthermore, it is proposed that NO can modulate tumor aggression in breast carcinoma through the inhibition of enzymes linked to DNA repair machinery [114] [115]. However, the latter source suggests that while there were increased levels of NO in breast cancer patients, there was no correlation between metastatic and non-metastatic patients, indicating that NO is not involved in such events.…”

Are NHE1 and inducible nitric oxide synthase involved in human ovarian cancer?

“…Since in several human diseases the NOS activity and pH are altered and affect a variety of processes including tumour cells metabolism [1,3,4,11,12,14], and expression and activity of H + exchangers (mainly NHE1) are increased in tumour cells [4][5][6][7][8], we propose that human ovarian cancer cells will show a potential functional link between increase in NO synthesis and low pHo, but higher pHi (Figure 1). The role of NHE1 seems crucial in this phenomenon, which also generates a pro-inflammatory environment maintaining elevated iNOS expression and NO synthesis.…”

“…Gynaecological cancers associate with alterations in the synthesis of key molecules, including nitric oxide (NO), a gas involved in cell signalling modulating cell proliferation and metabolism [1]. The NO has a dual effect, acting as a tumour promoter or by preventing tumour growth in different types of cancer [1].…”

“…The NO has a dual effect, acting as a tumour promoter or by preventing tumour growth in different types of cancer [1]. Intracellular alkalization and extracellular acidification result in increased NO synthesis by the NO synthase (NOS) isoform mainly expressed in endothelial cells (eNOS) leading to abnormal vascular reactivity [2].…”