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Abstract
6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6-phosphogluconate into ribulose-5-phosphate with NADP+ as cofactor in the pentose phosphate pathway (PPP). 6PGD is commonly upregulated and plays important roles in many human cancers, while the mechanism underlying such roles of 6PGD remains elusive. Here we show that upon EGFR activation, 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP+ and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. Abrogating 6PGD Y481 phosphorylation (pY481) dramatically attenuates EGF-promoted glioma cell proliferation, tumor growth and resistance to ionizing radiation. In addition, 6PGD pY481 is associated with Fyn expression, the malignancy and prognosis of human glioblastoma. These findings establish a critical role of Fyn-dependent 6PGD phosphorylation in EGF-promoted tumor growth and radiation resistance.
Highlights
6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6phosphogluconate into ribulose-5-phosphate with NADP+ as cofactor in the pentose phosphate pathway (PPP). 6PGD is commonly upregulated and plays important roles in many human cancers, while the mechanism underlying such roles of 6PGD remains elusive
Flag-6PGD proteins were immunoprecipitated from U87/ epidermal growth factor receptor (EGFR), U251/EGFR, or GSC11 cells stably expressing Flag-6PGD WT or Flag-6PGD Y481F with or without EGF treatment for 6PGD activity assays, which showed that EGF treatment increased the enzymatic activity of 6PGD WT, but failed to increase that of 6PGD Y481F (Figs. 1g, h, Supplementary Fig. 1e–h)
As nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial antioxidant, we examined the intracellular reactive oxygen species (ROS) levels in these tumor cells, which showed that tumor cells rescued with r6PGD WT had similar intracellular ROS levels with the cells rescued with r6PGD Y481F (Fig. 4c, Supplementary Fig. 4c)
Summary
6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6phosphogluconate into ribulose-5-phosphate with NADP+ as cofactor in the pentose phosphate pathway (PPP). 6PGD is commonly upregulated and plays important roles in many human cancers, while the mechanism underlying such roles of 6PGD remains elusive. These findings establish a critical role of Fyn-dependent 6PGD phosphorylation in EGF-promoted tumor growth and radiation resistance. It can be used to produce glutathione (GSH), which in turn eliminates reactive oxygen species (ROS) that is produced during cell proliferation and generated by other stimuli, such as ionizing radiation (IR) and radical-generating compounds[6,7] Another product R-5-P is a precursor for de novo, as well as salvage pathway of nucleic acid biogenesis that is important for mitosis and DNA repair[8]. 6-Phosphogluconate dehydrogenase (6PGD) is the third enzyme of the PPP that catalyzes the oxidative decarboxylation of 6-phosphogluconate (6-PG) to ribulose-5-phosphate (Ru-5-P) with concomitant reduction of NADP+ to NADPH This protein often functions as a homodimer[9]. How EGFR signaling reprograms cell metabolism to support GBM progression, especially the resistance to treatment, remains unclear
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