Title | G6PD-mediated increase in de novo NADP biosynthesis promotes antioxidant defense and tumor metastasis. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Zhang, Y, Xu, Y, Lu, W, Li, J, Yu, S, Brown, EJ, Stanger, BZ, Rabinowitz, JD, Yang, X |
Journal | Sci Adv |
Volume | 8 |
Issue | 29 |
Pagination | eabo0404 |
Date Published | 2022 Jul 22 |
ISSN | 2375-2548 |
Keywords | Antioxidants, 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> |
DOI | 10.1126/sciadv.abo0404 |
Alternate Journal | Sci Adv |
PubMed ID | 35857842 |
PubMed Central ID | PMC9299539 |
Grant List | R01 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 |