Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism

Polat, Ibrahim H.; Tarrado‐Castellarnau, Míriam; Bharat, Rohit; Perarnau, Jordi; Benito, Adrián; Cortés, Roberto; Sabatier, Philippe; Cascante, Marta

doi:10.3390/biology10020085

Cited by 19 publications

(24 citation statements)

References 66 publications

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“…Associated with this, Jiang et al have demonstrated that the inhibition of both the oxidative phase of the PPP and IDH enhances ROS levels in lung cancer cells [64]. Similarly, we have previously reported an increased glutamine consumption in breast cancer cells with ablated 6-phosphogluconate dehydrogenase, the third enzyme of the oxidative PPP [9], and that glutamine deprivation enhances ME flux in breast cancer cells [65], indicating strong crosstalk between glutamine metabolism and ox-PPP. Thus, we hypothesized that there might be a relation between G6PD and glutamine-dependent reactions for NADPH production.…”

Section: Discussionsupporting

confidence: 72%

“…We found that in both HT29 and HCT116 cell lines, the siG6PD pool decreased G6PD enzyme activity by over 80%, and western blot analysis demonstrated a visible decrease in the protein levels of this enzyme (Figure 2B,C and Supplementary Figure S1B). Several studies have shown that PPP has an essential role in cell growth and proliferation [9,10,[33][34][35][36]. Considering this, we examined the role of the G6PD enzyme in the proliferation of colon cancer cell models.…”

Section: G6pd Inhibition Alters the Proliferation Of Ht29 And Hct116 Cellsmentioning

confidence: 99%

“…As shown in Figure 3A,B, both HT29 and HCT116 colon cancer cells cultured in glutamine-free media exhibited a reduced proliferation rate compared to cells cultured in a complete medium. Several studies have shown that PPP has an essential role in cell growth and proliferation [9,10,[33][34][35][36]. Considering this, we examined the role of the G6PD enzyme in the proliferation of colon cancer cell models.…”

Section: Glutamine Deprivation Reduces Cell Proliferation and Leads To Cell Cycle Arrest And Apoptosismentioning

confidence: 99%

“…Both DNA and RNA are polymers of nucleotides, each of which requires a pentose sugar (deoxyribose for DNA and ribose for RNA) obtained via the PPP, giving this pathway an essential role in nucleotide synthesis. Furthermore, PPP also produces metabolism in breast cancer cells, since the inhibition of the 6PGD enzyme led to enhanced glutaminolysis and increased activities of some enzymes involved in glutamine metabolism such as the malic enzyme (ME) and isocitrate dehydrogenase (IDH) [9].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, PPP also produces the reducing equivalents, NADPH, which not only are involved in the regulation of reactive oxygen species (ROS) through the maintenance of reduced glutathione (GSH) pool, but also serve as cofactors in the biosynthesis of several essential macromolecules, such as lipids and amino acids [ 5 , 6 , 7 ]. Besides serving as a crucial pathway for the biosynthesis and the maintenance of redox status, PPP also plays important roles in various aspects related to cancer cells viability, including proliferation, apoptosis, invasiveness, drug resistance, and metastasis [ 4 , 8 , 9 , 10 ]. Cancer cells are known to be significantly dependent on PPP to maintain their highly proliferative state [ 6 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells

et al. 2021

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Nucleotide pools need to be constantly replenished in cancer cells to support cell proliferation. The synthesis of nucleotides requires glutamine and 5-phosphoribosyl-1-pyrophosphate produced from ribose-5-phosphate via the oxidative branch of the pentose phosphate pathway (ox-PPP). Both PPP and glutamine also play a key role in maintaining the redox status of cancer cells. Enhanced glutamine metabolism and increased glucose 6-phosphate dehydrogenase (G6PD) expression have been related to a malignant phenotype in tumors. However, the association between G6PD overexpression and glutamine consumption in cancer cell proliferation is still incompletely understood. In this study, we demonstrated that both inhibition of G6PD and glutamine deprivation decrease the proliferation of colon cancer cells and induce cell cycle arrest and apoptosis. Moreover, we unveiled that glutamine deprivation induce an increase of G6PD expression that is mediated through the activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2). This crosstalk between G6PD and glutamine points out the potential of combined therapies targeting oxidative PPP enzymes and glutamine catabolism to combat colon cancer.

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Section: Discussionsupporting

confidence: 72%

Section: G6pd Inhibition Alters the Proliferation Of Ht29 And Hct116 Cellsmentioning

confidence: 99%

Section: Glutamine Deprivation Reduces Cell Proliferation and Leads To Cell Cycle Arrest And Apoptosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells

et al. 2021

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Natural flavonoids as promising 6‐phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments

Adem,

Yırtıcı,

Aydın

et al. 2023

Archiv der Pharmazie

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The primary strategy in the fight against cancer is to screen compounds that may be effective on different types of cancer. Compounds from plants seem to be a good source. The present study investigated the inhibitory effects of some flavonoids on the 6‐phosphogluconate dehydrogenase (6‐PGD) enzyme. We determined that quercetin, myricetin, fisetin, morin, apigenin, and baicalein exhibited powerful inhibition effects with IC50 values between 4.08 and 21.26 µM, while luteolin, kaempferol, apiin, galangin, and baicalin showed moderate effects with IC50 values between 54.15 and 138.91 µM. Quercetin competitively inhibited the binding of NADP and 6‐phosphogluconate to the 6‐PGD enzyme with Ki values of 0.527 ± 0.251 and 0.374 ± 0.138 µM, respectively. We calculated Ki values using the Cheng–Prusoff equation as between 0.44 and 14.88 µM. The possible interaction details of polyphenols with the active site of 6‐PGD were analyzed with docking software. In silico and in vitro studies indicated that the –OH groups on the A and C ring of flavonoids bind to the enzyme's active site via hydrogen bonding, while the –OH groups on the C ring contributed significantly to the increase in the inhibitory potentials of the molecules. Molecular dynamic simulations tested the stability of the 6‐PGD‐quercetin complex during 100 ns. These phytochemicals were suitable for drug use when optimized with absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria. The effects of the studied compounds on cancer cell lines of potential targets were demonstrated by network analysis. In conclusion, this study suggests that flavonoids found to be potent inhibitors could serve as leading candidates to treat many cancers via 6‐PGD inhibition.

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Transcriptome Profiling in the Marine Red Alga Neopyropia yezoensis Under Light/Dark Cycle

Mizuta

Uji

2022

Mar Biotechnol

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Many organisms are subjected to a daily cycle of light and darkness, which significantly influences metabolic and physiological processes. In the present study, Neopyropia yezoensis, one of the major cultivated seaweeds used in "nori," was harvested in the morning and evening during light/dark treatments to investigate daily changes in gene expression using RNA-sequencing. A high abundance of transcripts in the morning includes the genes associated with carbon-nitrogen assimilations, polyunsaturated fatty acid, and starch synthesis. In contrast, the upregulation of a subset of the genes associated with the pentose phosphate pathway, cell cycle, and DNA replication at evening is necessary for the tight control of light-sensitive processes, such as DNA replication. Additionally, a high abundance of transcripts at dusk encoding asparaginase and glutamate dehydrogenase imply that regulation of asparagine catabolism and tricarboxylic acid cycle possibly contributes to supply nitrogen and carbon, respectively, for growth during the dark. In addition, genes encoding cryptochrome/photolyase family and histone modification proteins were identified as potential key players for regulating diurnal rhythmic genes.

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Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism

Cited by 19 publications

References 66 publications

Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells

Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells

Natural flavonoids as promising 6‐phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments

Transcriptome Profiling in the Marine Red Alga Neopyropia yezoensis Under Light/Dark Cycle

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