Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

Aurora, Arin B.; Khivansara, Vishal; Leach, Ashley; Gill, Jennifer G.; Martin-Sandoval, Misty S.; Yang, Chendong; Kasitinon, Stacy Y.; Bezwada, Divya; Tasdogan, Alpaslan; Gu, Wen; Mathews, Thomas P.; Zhao, Zhiyu; DeBerardinis, Ralph J.; Morrison, Sean J.

doi:10.1073/pnas.2120617119

Cited by 46 publications

(23 citation statements)

References 67 publications

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“…Combined, these data suggest that the major metabolic features distinguishing the LAMP2A-KO from WT tumors are the PPP and mitochondrial metabolism, both required to support a high proliferation rate. Further, consistent with the findings that metastasizing melanoma cells depend on G6PD 26 , our findings signify that LAMP2A deficient cancer cells undergo a metabolic switch to become more reliant on G6PD and PPP function.…”

Section: Resultssupporting

confidence: 90%

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Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

Zhou

Shi

Shirokova

et al. 2022

Preprint

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The role of chaperone-mediated autophagy (CMA) in cancer initiation and progression is not well understood due to the lack of a loss-of-function cancer models of LAMP2A, the key regulator of this process. Here, by generating an isoform-specific knockout of LAMP2A, we show that CMA deficiency promotes proliferation and tumor growth in human cancers of mesenchymal origin. Accordingly, we observed that LAMP2A diminishes in metastatic lesions compared to matched primary human tumors from the same patients. Loss of CMA enhanced TGF-beta signaling in tumors, rewired the tumor metabolome to promote anabolic pathways and mitochondrial metabolism, meeting the metabolic requirements of rapid growth. Mechanistically, we show that TGF-betaR2 enhances the enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), to promote the generation of nucleotides. Consequently, pharmacological inhibition of TGF-beta signaling in LAMP2A-KO cells suppresses G6PD activity, mitochondrial metabolism, and proliferation to WT levels. Conversely, pharmacological inhibition of mitochondrial metabolism suppressed LAMP2A-KO driven proliferation. Overall, our study provides a molecular mechanism on the CMAs tumor-suppressive function by connecting two important oncogenic pathways, the TGF-beta signaling and PPP metabolism, to the loss-of-function LAMP2A in mesenchymal cancer types.

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Section: Resultssupporting

confidence: 90%

“…Further, consistent with the findings that metastasizing melanoma cells depend on G6PD 26 , our findings signify that LAMP2A deficient cancer cells undergo a metabolic switch to become more reliant on G6PD and PPP function.…”

Section: Cma Deficiency Rewires the Tumor Metabolomesupporting

confidence: 90%

Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

Zhou

Shi

Shirokova

et al. 2022

Preprint

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“…One explanation for this is the paradoxical finding by Zhao et al that in A549 cells, the constitutive activation of NRF2 results in both high expression of oxidative PPP enzymes and reduced dependence on the oxidative PPP for cell growth [15]. Another study in melanoma cells, which also have high PPP activity, found that when G6PD function was impaired, there was no reduction in erythrose-4-phosphate levels [26]. These studies demonstrate that cancer cells are resilient to G6PD inhibition and may continue to fuel the non-oxidative PPP through alternative methods.…”

Section: Discussionmentioning

confidence: 99%

Erythritol synthesis in human cells is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway

Ortiz

Heinz

Hiller

et al. 2022

Preprint

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Erythritol is a predictive biomarker of cardiometabolic diseases and is produced from glucose metabolism through the pentose phosphate pathway (PPP). Little is known regarding the regulation of endogenous erythritol synthesis in humans. In the present study, we investigated the stimuli that promote erythritol synthesis in human cells and characterized potential points of regulation along the PPP. Human A549 lung carcinoma cells were chosen for their known ability to synthesize erythritol. A549 cells were treated with potential substrates for erythritol production, including glucose, fructose, and glycerol. Using siRNA knockdown, we assessed the necessity of enzymes G6PD, TKT, TALDO, and SORD for erythritol synthesis. We also used position-specific 13C-glucose tracers to determine whether the carbons for erythritol synthesis are derived directly from glycolysis or through the oxidative PPP. Finally, we assessed if erythritol synthesis responds to oxidative stress using chemical and genetic models. Intracellular erythritol was directly associated with media glucose concentration. In addition, siRNA knockdown of TKT or SORD inhibited erythritol synthesis, whereas siG6PD did not. Both chemically induced oxidative stress and constitutive activation of the antioxidant response transcription factor NRF2 elevated intracellular erythritol. Our findings indicate that erythritol synthesis is proportional to flux through the PPP and is regulated by non-oxidative PPP enzymes.

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“…The concentrations of 6-An thus should be considered when it is used to inhibit G6PD enzyme activity. 6-An does not affect G6PD, but instead, blocks 6PGD( Aurora et al, 2022 ). Earlier in vivo studies revealed that 6-An inhibits the carbon-atom transfer from glucose to ribose and suppresses oxPPP ( Köhler et al, 1970 ).…”

Section: Inhibitorsmentioning

confidence: 97%

Recent findings in the regulation of G6PD and its role in diseases

et al. 2022

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Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers. In addition, G6PD may act as a regulator of viral replication and vascular smooth muscle function. Therefore, G6PD-mediated activation of PPP may promote tumor and non-neoplastic disease progression. Recently, studies have identified post-translational modifications (PTMs) as an important mechanism for regulating G6PD function. Here, we provide a comprehensive review of various PTMs (e.g., phosphorylation, acetylation, glycosylation, ubiquitination, and glutarylation), which are identified in the regulation of G6PD structure, expression and enzymatic activity. In addition, we review signaling pathways that regulate G6PD and evaluate the role of oncogenic signals that lead to the reprogramming of PPP in tumor and non-neoplastic diseases as well as summarize the inhibitors that target G6PD.

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Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

Cited by 46 publications

References 67 publications

Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

Erythritol synthesis in human cells is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway

Recent findings in the regulation of G6PD and its role in diseases

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