The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers

Abstract

Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges—including side effects—still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy.

Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic–Angiogenic Pathway

“…It is known that HIF is an important metabolic regulator associated with glucose-6-phosphate dehydrogenase (G6PD) [62], but it is also known, based on literature findings on the correlation between HIF-1α and NAD(P)H Quinone Dehydrogenase 1 (NQO1), that increased expression of the transcriptional factor is observed to be accompanied by an increase of NQO1. Thus, it is plausible to conclude that the compound VP18/58's inhibitory activity towards both HIF-α and HO-1 should reflect inhibition of downstream gene/protein expression of this factor together with pentose-phosphate-pathway-related genes [62][63][64][65].…”

The Role of Glucose-6-phosphate Dehydrogenase in the Wine Yeast Hanseniaspora uvarum

“…Predisposition for this enzymopathic condition may affect as many as 500 million people worldwide, most being asymptomatic unless exposed to certain diets or drugs [9]. In addition, increased enzyme activities have been detected in a variety of human tumors [10].…”