Abstract
The pentose phosphate pathway (PPP) is a branch from glycolysis that begins from glucose-6-phosphate (G6P) and ends up with fructose-6-phosphate (F6P) and glyceraldehyde-3-phosphate (GADP). Its primary physiological significance is to provide nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotides for vital activities such as reactive oxygen species (ROS) defense and DNA synthesis. Glucose-6-phosphate dehydrogenase (G6PD) is a housekeeping protein with 514 amino acids that is also the rate-limiting enzyme of PPP, catalyzing G6P into 6-phosphogluconolactone (6PGL) and producing the first NADPH of this pathway. Increasing evidence indicates that G6PD is upregulated in diverse cancers, and this dysfunction influences DNA synthesis, DNA repair, cell cycle regulation and redox homeostasis, which provides advantageous conditions for cancer cell growth, epithelial-mesenchymal transition (EMT), invasion, metastasis and chemoresistance. Thus, targeting G6PD by inhibitors has been shown as a promising strategy in treating cancer and reversing chemotherapeutic resistance. In this review, we will summarize the existing knowledge concerning G6PD and discuss its role, regulation and inhibitors in cancer development and chemotherapy resistance.
Highlights
Accepted: 8 February 2022Basic metabolism, including lipid metabolism, glucose metabolism, protein metabolism and so on, is a basic characteristic of life activity that is essential in achieving material interchange, self-renewal and homeostasis maintenance
The overexpression of Glucose-6-phosphate dehydrogenase (G6PD) influences DNA synthesis, DNA repair, cell cycle regulation, redox equilibrium, proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis to provide an advantageous condition for cancer cells [28,29,30,31,32]
Trols G6PD expression through two steps by inhibiting G6PD pre-mRNA splicing, wh suggests that G6PD is a key regulatory factor of phosphatase and tensinphosphorylation homolog (PTEN) in controlling tumor progress and implies that G6PD is a valuable target for anticancer treatments
Summary
Basic metabolism, including lipid metabolism, glucose metabolism, protein metabolism and so on, is a basic characteristic of life activity that is essential in achieving material interchange, self-renewal and homeostasis maintenance. Glucose absorbed extracellularly or transformed from other macromolecules is one of the primary carbon sources, and its catabolism mainly includes glycolysis, the TCA cycle and the pentose phosphate pathway (PPP). The catabolism of glucose provides nicotinamide adenine dinucleotide phosphate (NADPH), nucleotides and ATP and supports lipid and amino acids synthesis for a variety of biological activities. PPP, known as pentose phosphate shunt, is unlike glycolysis and the TCA cycle, because ATP is not produced in this pathway. Instead, it is the main source of NADPH, which is the primary reducing equivalent source for reactive oxygen species (ROS) defense and DNA synthesis. We will discuss the characteristics of G6PD, roles of G6PD in the development of cancer, inhibitors of G6PD and the mechanisms behind chemotherapy resistance caused by G6PD
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