G6PD-mediated increase in de novo NADP biosynthesis promotes antioxidant defense and tumor metastasis.

TitleG6PD-mediated increase in de novo NADP biosynthesis promotes antioxidant defense and tumor metastasis.
Publication TypeJournal Article
Year of Publication2022
AuthorsZhang, Y, Xu, Y, Lu, W, Li, J, Yu, S, Brown, EJ, Stanger, BZ, Rabinowitz, JD, Yang, X
JournalSci Adv
Volume8
Issue29
Paginationeabo0404
Date Published2022 Jul 22
ISSN2375-2548
KeywordsAntioxidants, Glucosephosphate Dehydrogenase, Humans, NADP, Oxidation-Reduction, Pancreatic Neoplasms
Abstract

<p>Metastasizing cancer cells are able to withstand high levels of oxidative stress through mechanisms that are poorly understood. Here, we show that under various oxidative stress conditions, pancreatic cancer cells markedly expand NADPH and NADP pools. This expansion is due to up-regulation of glucose-6-phosphate dehydrogenase (G6PD), which stimulates the cytoplasmic nicotinamide adenine dinucleotide kinase (NADK1) to produce NADP while converting NADP to NADPH. G6PD is activated by the transcription factor TAp73, which is, in turn, regulated by two pathways. Nuclear factor-erythroid 2 p45-related factor-2 suppresses expression of the ubiquitin ligase PIRH2, stabilizing the TAp73 protein. Checkpoint kinases 1/2 and E2F1 induce expression of the gene. Levels of G6PD and its upstream activators are elevated in metastatic pancreatic cancer. Knocking down G6PD impedes pancreatic cancer metastasis, whereas forced G6PD expression promotes it. These findings reveal an intracellular network that maintains redox homeostasis through G6PD-mediated increase in de novo NADP biosynthesis, which may be co-opted by tumor cells to enable metastasis.</p>

DOI10.1126/sciadv.abo0404
Alternate JournalSci Adv
PubMed ID35857842
PubMed Central IDPMC9299539
Grant ListR01 CA243520 / CA / NCI NIH HHS / United States
R01 CA235760 / CA / NCI NIH HHS / United States
P30 ES013508 / ES / NIEHS NIH HHS / United States
R01 CA184867 / CA / NCI NIH HHS / United States
R50 CA211437 / CA / NCI NIH HHS / United States
T32 CA115299 / CA / NCI NIH HHS / United States
R01 CA182675 / CA / NCI NIH HHS / United States