NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism

Chen, Li; Zhang, Zhaoyue; Hoshino, Atsushi; Zheng, Henry D.; Morley, Michael; Arany, Zoltàn; Rabinowitz, Joshua D.

doi:10.1038/s42255-019-0043-x

Cited by 251 publications

(327 citation statements)

References 43 publications

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“…Cancer cells express pyruvate kinase 2 (PKM2), a growth signal-sensitive form of the rate-limiting enzyme in the last step of glycolysis 3 , leading to the accumulation of glycolytic intermediates. The accumulated glycolytic intermediates can branch into the PPP for nucleotide biosynthesis and NADPH production, which is important for cell proliferation and redox state maintenance 4 . The PPP is highly upregulated in cancers to meet the needs of uncontrolled cell proliferation 5,6 .…”

mentioning

confidence: 99%

TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

et al. 2020

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PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

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confidence: 99%

TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

et al. 2020

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“…The pentose phosphate pathway (PPP) is a major contributor to the cellular NADPH pool [ 41 ]. NADPH is critical for the synthesis of fatty acids, cholesterol, mevalonate pathway products [ 42 ], nucleotides, folate [ 41 , 43 ], and proline [ 40 ], all of which can support tumorigenesis. NADPH is also important for survival during ROS-mediated stress as a result of extracellular matrix (ECM) detachment [ 44 ].…”

Section: Modulation Of Metabolic Processes By Nrf2mentioning

confidence: 99%

“…Overall, these studies demonstrate the importance of KEAP1 mutational status when evaluating sensitivity to PPP inhibition in a therapeutic context. However, recent work suggests that the oxidative PPP plays a unique role in folate metabolism [ 41 ]. Chen et al demonstrated that while the PPP, IDH1 and ME1 could all support cellular proliferation, only the PPP could maintain a normal NADPH/NADP+ ratio.…”

Section: Modulation Of Metabolic Processes By Nrf2mentioning

confidence: 99%

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

DeBlasi

DeNicola

2020

Cancers

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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

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“…Catalases and the glutathione pathway which scavenge ROS from the cell require NADPH ( Toledano et al, 2013 ; Gómez et al, 2019 ). Interestingly, not only are oxidative stress response proteins differentially expressed during treatment with phenolic inhibitors, as revealed in a proteomics screen, but also flux is moved toward the pentose phosphate pathway ( Lv et al, 2014 ), one of the main metabolic pathways that generate cytosolic NADPH ( Chen et al, 2019 ). Indeed, this proteomic study is corroborated by a functional genomic screen which showed that pentose phosphate pathway mutants accumulated ROS and were hypersensitive to coniferyl aldehyde ( Fletcher et al, 2019 ).…”

Section: Mining Genome-wide Studies To Identify Common Approaches To mentioning

confidence: 99%

Multi-Faceted Systems Biology Approaches Present a Cellular Landscape of Phenolic Compound Inhibition in Saccharomyces cerevisiae

Fletcher

Baetz

2020

Front. Bioeng. Biotechnol.

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Synthetic biology has played a major role in engineering microbial cell factories to convert plant biomass (lignocellulose) to fuels and bioproducts by fermentation. However, the final product yield is limited by inhibition of microbial growth and fermentation by toxic phenolic compounds generated during lignocellulosic pre-treatment and hydrolysis. Advances in the development of systems biology technologies (genomics, transcriptomics, proteomics, metabolomics) have rapidly resulted in large datasets which are necessary to obtain a holistic understanding of complex biological processes underlying phenolic compound toxicity. Here, we review and compare different systems biology tools that have been utilized to identify molecular mechanisms that modulate phenolic compound toxicity in Saccharomyces cerevisiae. By focusing on and comparing functional genomics and transcriptomics approaches we identify common mechanisms potentially underlying phenolic toxicity. Additionally, we discuss possible ways by which integration of data obtained across multiple unbiased approaches can result in new avenues to develop yeast strains with a significant improvement in tolerance to phenolic fermentation inhibitors.

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NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism

Cited by 251 publications

References 43 publications

TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

Multi-Faceted Systems Biology Approaches Present a Cellular Landscape of Phenolic Compound Inhibition in Saccharomyces cerevisiae

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