Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Abstract

Nitric oxide (NO) is a signaling molecule that plays important roles in diverse biological processes and thus its dysregulation is involved in the pathogenesis of various disorders. In cancer, NO has broad and sometimes dichotomous roles; it is involved in cancer initiation and progression, but also restricts cancer proliferation and invasion, and contributes to the anti-tumor immune response. The importance of NO in a range of cellular processes is exemplified by its tight spatial and dosage control at multiple levels, including via its transcriptional, post-translational and metabolic regulation. In this Review, we focus on the regulation of NO via the synthesis and availability of its precursor, arginine, and discuss the implications of this metabolic regulation for cancer biology and therapy. Despite the established contribution of NO to cancer pathogenesis, the implementation of NO-related cancer therapeutics remains limited, likely due to the challenge of targeting and inducing its protective functions in a cell- and dosage-specific manner. A better understanding of how arginine regulates the production of NO in cancer might thus support the development of anti-cancer drugs that target this key metabolic pathway, and other metabolic pathways involved in NO production.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…Reduced arginine up-take by inflamed colon may cause amino acid increase in circulation, which would explain a direct correlation between systemic arginine and the severity of endoscopic inflammation observed in this study. Such an explanation is supported by the observation that ADMA and SDMA, competitors for amino acid transporters [10], were independent predictors of systemic arginine, specifically in active UC. Unlike in other studies [21], active CD here was associated with diminished systemic arginine concentrations and, like in other studies [24], no difference in the case of UC was observed.…”

“…PRMT2 was an exception as it was also upregulated in the inflamed small bowel, whereas in the large bowel, it was more markedly overexpressed in quiescent tissue than inflamed derived from UC patients. Concerning the L-arginine/NO pathway, PRMTs act as negative effectors of NO synthesis by increasing the pool of ADMA and SDMA, inhibitors of NOSs, and competitors for arginine transporters [10]. Taking into account accelerated NO synthesis in IBD and its contribution to the disease pathogenesis [7], the up-regulation of PRMTs might be viewed as beneficial.…”

MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion

“…31). NO can exhibit both anti-and protumor effects, and has been shown to regulate angiogenesis, apoptosis, cell cycle, invasion, and metastasis (32). Polyamines are highly regulated organic cations that are elevated in proliferating tissues including various cancers (31).…”

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

“…However, a marked cytotoxic effect of MET was observed in co-culture systems, which is in agreement with previous in vitro studies, carried out on BT-20 breast cancer cell line (45). In MOs, as well as in other cells especially macrophages, the amino acid L-arginine is also used as a substrate by arginase to produce polyamines (46) that contribute to the tumor progression (47), and by iNOS to produce NO (46), which has antitumor effects at high levels (48). The current study provides evidence that MOs cultured with breast cancer cells exhibited high levels of iNOS, but remain without marked change when treated with MET.…”