Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance

Liu, Ruilong; Li, Wenfeng; Tao, Bei; Wang, Xiongjun; Yang, Zhuo; Zhang, Yajuan; Wang, Chenyao; Liu, Rongzhi; Gao, Hong; Ji, Liang; Yang, Weiwei

doi:10.1038/s41467-019-08921-8

Cited by 79 publications

(64 citation statements)

References 37 publications

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“… 53 – 55 Both the phosphorylation of PGD at Y481 upon EGFR activation and acetylation of PGD at K76 and K294 by acetyltransferases enhance its activation for producing NADPH in cancer cells. 56 , 57 Conversely, protein kinase A (PKA) inhibits G6PD activity by directly phosphorylating it on serine and threonine residues. 58 Additionally, G6PD activity can be regulated by several signaling pathways in tumors, such as the PI3K/AKT, Ras, Src, Nrf2, mTORC1, PETEN, ATM, and TP53 pathways, in a direct or indirect manner (reviewed in refs.…”

Section: Molecular Mechanisms Of Nadph Homeostasis In Cancermentioning

confidence: 99%

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

Lin

Tian

et al. 2020

Sig Transduct Target Ther

269

196

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Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.

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Section: Molecular Mechanisms Of Nadph Homeostasis In Cancermentioning

confidence: 99%

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

Lin

Tian

et al. 2020

Sig Transduct Target Ther

269

196

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“…Increased PPP activity induces high levels of ROS. This is counteracted by an adaptive response that is found with the use of chemotherapeutic agents [26,32,246], radiation [247,248,249,250], and oxidative agents [28,239,251]. Drug-resistant cancer cell lines display increased G6PD activity and increased intracellular glutathione concentrations indicative of oxidative PPP.…”

Section: G6pd/ppp As An Anticancer Targetmentioning

confidence: 99%

The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer

Yang

Yen

et al. 2019

Cells

171

132

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The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. NADPH also plays key roles in cellular processes mediated by redox signaling. Insufficient G6PD activity predisposes cells to growth retardation and demise. Severely lacking G6PD impairs embryonic development and delays organismal growth. Altered G6PD activity is associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, as well as diabetes and hypertension. Aberrant activation of G6PD leads to enhanced cell proliferation and adaptation in many types of cancers. The present review aims to update the existing knowledge concerning G6PD and emphasizes how G6PD modulates redox signaling and affects cell survival and demise, particularly in diseases such as cancer. Exploiting G6PD as a potential drug target against cancer is also discussed.

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“…EGFR antagonists) could be readily adapted from cancer therapeutics for laminitis treatment. The EGFR and its ligands are overexpressed in many human cancers, and dysregulation of the EGF/R network at multiple levels signals a poor prognosis [28–30]. However, in the current study there was no evidence of an increased expression (neither gene nor protein) of the lamellar EGFR during experimentally-induced laminitis, nor were there increased concentrations of EGF (either during the model or in ponies prone to laminitis), which suggests that the EGF system is not central to the pathogenesis of laminitis.…”

Section: Discussionmentioning

confidence: 99%

An investigation of the equine epidermal growth factor system during hyperinsulinemic laminitis

et al. 2019

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Equine laminitis is a disease of the digital epidermal lamellae typified by epidermal cell proliferation and structural collapse. Most commonly the disease is caused by hyperinsulinemia, although the pathogenesis is incompletely understood. Insulin can activate the epidermal growth factor (EGF) system in other species and the present study tested the hypothesis that upregulation of EGF receptor (EGFR) signalling is a key factor in laminitis pathophysiology. First, we examined lamellar tissue from healthy Standardbred horses and those with induced hyperinsulinemia and laminitis for EGFR distribution and quantity using immunostaining and gene expression, respectively. Phosphorylation of EGFR was also quantified. Next, plasma EGF concentrations were compared in healthy and insulin-infused horses, and in healthy and insulin-dysregulated ponies before and after feeding. The EGFR were localised to the secondary epidermal lamellae, with stronger staining in parabasal, rather than basal, cells. No change in EGFR gene expression occurred with laminitis, although the receptor showed some phosphorylation. No difference was seen in EGF concentrations in horses, but in insulin-dysregulated ponies mean, post-prandial EGF concentrations were almost three times higher than in healthy ponies (274 ± 90 vs. 97.4 ± 20.9 pg/mL, P = 0.05). Although the EGFR does not appear to play a major pathogenic role in hyperinsulinemic laminitis, the significance of increased EGF in insulin-dysregulated ponies deserves further investigation.

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Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance

Cited by 79 publications

References 37 publications

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer

An investigation of the equine epidermal growth factor system during hyperinsulinemic laminitis

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