The Multiple Roles of Glucose-6-Phosphate Dehydrogenase in Tumorigenesis and Cancer Chemoresistance

Song, Jiaqi; Sun, Huanran; Zhang, Shuai; Shan, Changliang

doi:10.3390/life12020271

Cited by 48 publications

(34 citation statements)

References 111 publications

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“…G6PD-deficient individuals are susceptible to the development of favism, neonatal jaundice and infection/drug-induced hemolysis primarily due to oxidative stress [ 30 ]. An increasing body of evidence in the last decade has documented the aberrantly high expression of G6PD in several types of cancers [ 11 , 13 , 15 , 31 ]. Thus, our study was aimed to determine the oncogenic role of G6PD in promoting cellular proliferation, survival and chemotherapeutic drug resistance in MM.…”

Section: Discussionmentioning

confidence: 99%

“…Mounting evidence has demonstrated that G6PD expression is upregulated in several types of cancers and it promotes tumor progression [ 15 ]. Inhibition of G6PD has emerged as a potential therapeutic strategy for cancer treatment, such as the application of the small molecule G6PD inhibitor RRX-001 in colorectal cancer and hepatoma cells [ 16 – 18 ], and the endogenous G6PD inhibitor dehydroepiandrosterone (DHEA: 5-androsten-3beta-ol-17-one) in cervical and breast cancer cells [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activating Wnt/β-catenin pathway

et al. 2022

Exp Hematol Oncol

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Background Glucose-6-phosphate dehydrogenase (G6PD) as the rate-limiting enzyme in the pentose phosphate pathway (PPP) is well-established as an aberrantly expressed protein in numerous clinical diseases; however, its role in cancer, specifically in multiple myeloma (MM) remains elusive. Methods In this study, serum metabolites in 70 normal people and 70 newly diagnosed MM patients were analyzed using untargeted metabolomics and the results were verified using ELISA. The survival analysis of multiple clinical datasets was performed to identify a potential target gene in MM. The oncogenic role of G6PD was investigated using lentivirus-based overexpression or knockdown of G6PD using RNAi or an inhibitor in vitro, and in a xenograft mouse model in vivo. The mechanisms of induced Dexamethasone (Dexa)-resistance of G6PD were further explored using the above established MM cell lines in vitro. Results Based on the screening of potential genes, PPP was shown to be involved in the occurrence of MM, which was evidenced by the differential expression of serum metabolites of G6P and Dehydroepiandrosterone sulfate (DHEAS, the more stable sulfate ester form of an endogenously uncompetitive G6PD inhibitor known as DHEA). Elevated G6PD promoted MM cell proliferation. Mechanistically, high G6PD expression enhanced enzymatic generation of the antioxidant NADPH via the PPP and decreased the production of reactive oxygen species (ROS), thus inducing the proliferation and Dexa resistance in MM cells. Furthermore, canonical Wnt/β-catenin signaling also participated in regulating G6PD-induced drug resistance and cellular redox levels of ROS. Intriguingly, DHEA treatment could enhance the sensitivity of MM cells to Dexa primarily through augmenting cellular oxidative stress. Conclusions Our data demonstrate that G6PD enhances the generation of the enzymatic anti-oxidant NADPH and decreases ROS generation, thereby promoting resistance to Dexa-induced apoptosis via the enzymatic PPP and non-enzymatic Wnt/β-catenin signaling pathway in MM. Targeting G6PD to harness cellular redox may serve as a promising novel strategy for the management of MM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activating Wnt/β-catenin pathway

et al. 2022

Exp Hematol Oncol

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“…Altogether, these results confirm the rationale for targeting G6PD activity in cancer. Indeed, targeting G6PD with inhibitors has been shown to be a promising strategy for the treatment of cancer [19]. Our results suggest that targeting G6PD with inhibitors in breast cancer patients that have a low level of RIP140 expression might be more efficient.…”

Section: Discussionmentioning

confidence: 75%

“…G6PD regulatory networks are complex in cancer cells, and multiple cis/trans elements regulate G6PD expression. At the transcriptional level, some transcription factors have been described to regulate G6PD expression in various cancers [19]. For instance, NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in clear-cell renal cell carcinoma [20].…”

Section: Discussionmentioning

confidence: 99%

The Transcription Coregulator RIP140 Inhibits Cancer Cell Proliferation by Targeting the Pentose Phosphate Pathway

Gitenay

Cavaillès

Teyssier

2022

IJMS

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Cancer cells switch their metabolism toward glucose metabolism to sustain their uncontrolled proliferation. Consequently, glycolytic intermediates are diverted into the pentose phosphate pathway (PPP) to produce macromolecules necessary for cell growth. The transcription regulator RIP140 controls glucose metabolism in tumor cells, but its role in cancer-associated reprogramming of cell metabolism remains poorly understood. Here, we show that, in human breast cancer cells and mouse embryonic fibroblasts, RIP140 inhibits the expression of the gene-encoding G6PD, the first enzyme of the PPP. RIP140 deficiency increases G6PD activity as well as the level of NADPH, a reducing cofactor essential for macromolecule synthesis. Moreover, G6PD knock-down inhibits the gain of proliferation observed when RIP140 expression is reduced. Importantly, RIP140-deficient cells are more sensitive to G6PD inhibition in cell proliferation assays and tumor growth experiments. Altogether, this study describes a novel role for RIP140 in regulating G6PD levels, which links its effect on breast cancer cell proliferation to metabolic rewiring.

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“…The aberrant activation of the EMT process accelerates malignancy and drug tolerance of several epithelial carcinomas ( Song et al, 2022 ). EMT progression is regulated by encoding genes, transcription factors, and Circulating exosomes ( Marimuthu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition

Zhang

Lan

et al. 2022

Front. Genet.

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Tumor metastasis and invasion are the main impediments to lung adenocarcinoma successful treatment. Previous studies demonstrate that chemotherapeutic agents can elevate the malignancy of cancer cells other than their therapeutic effects. In this study, the effects of transient low-dose cisplatin treatment on the malignant development of lung adenocarcinoma cells (A549) were detected, and the underlying epigenetic mechanisms were investigated. The findings showed that A549 cells exhibited epithelial-mesenchymal transition (EMT)-like phenotype along with malignant progression under the transient low-dose cisplatin treatment. Meanwhile, low-dose cisplatin was found to induce contactin-1 (CNTN-1) upregulation in A549 cells. Subsequently, we found that further overexpressing CNTN-1 in A549 cells obviously activated the EMT process in vitro and in vivo, and caused malignant development of A549 cells in vitro. Taken together, we conclude that low-dose cisplatin can activate the EMT process and resulting malignant progression through upregulating CNTN-1 in A549 cells. The findings provided new evidence that a low concentration of chemotherapeutic agents could facilitate the malignancy of carcinoma cells via activating the EMT process other than their therapeutic effects.

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The Multiple Roles of Glucose-6-Phosphate Dehydrogenase in Tumorigenesis and Cancer Chemoresistance

Cited by 48 publications

References 111 publications

G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activating Wnt/β-catenin pathway

G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activating Wnt/β-catenin pathway

The Transcription Coregulator RIP140 Inhibits Cancer Cell Proliferation by Targeting the Pentose Phosphate Pathway

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition

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