Abstract
ABSTRACTNitric 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.
Highlights
Nitric oxide (NO) is a short-lived, gaseous signaling molecule that is produced endogenously by a family of enzymes called the nitric oxide synthases (NOS), which catalyze the synthesis of NO from the amino acid arginine (Bredt, 1999)
Unregulated NO production is implicated in multiple pathophysiological conditions, including cancer (Burke et al, 2013). In this Review, we summarize what is known about NO metabolism in carcinogenesis, focusing on the importance of arginine synthesis and its availability for NO production
The activity of the key enzymes involved in NO production, namely argininosuccinate synthase 1 (ASS1), argininosuccinate lyase (ASL), arginase and NOS, are frequently altered in various types of cancers, enabling us to identify vulnerabilities in NO-related pathways and to design novel anti-cancer drugs that target these enzymes
Summary
Nitric oxide (NO) is a short-lived, gaseous signaling molecule that is produced endogenously by a family of enzymes called the nitric oxide synthases (NOS), which catalyze the synthesis of NO from the amino acid arginine (Bredt, 1999). In certain physiological and pathological states, such as during infancy, growth, pregnancy and illness, such as infections and cancer, arginine is synthesized endogenously in multiple tissues by the arginine-citrulline cycle This is because the amount of circulating arginine, as derived from dietary intake and kidney production, cannot meet cellular requirements for arginine during these states (Fig. 1). In contrast to the four cellular enzymes that use arginine as a substrate, only ASL can generate endogenous arginine in mammalian cells (Fig. 1) Another important factor that regulates the intracellular availability of arginine for NOS is the activity of other competing enzymes that use arginine as a substrate. One of the main competitors is another urea cycle enzyme, arginase, which converts arginine
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