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The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH.

ABSTRACT: The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the "Warburg Effect". However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to prevent apoptosis, (ii) as a provision for the maintenance of energy by intermediate glycolysis, (iii) by increasing genomic material to the cellular pool of nucleic acid bases, (iv) by promoting survival through increasing glycolysis, and so increasing acid production, and (v) by inducing cellular proliferation by the synthesis of nucleic acid, fatty acid, and amino acid. Each step of the PPP can be upregulated in some types of cancer but not in others. An interesting aspect of this metabolic pathway is the shared regulation of the glycolytic and PPP pathways by intracellular pH (pHi). Indeed, as with glycolysis, the optimum activity of the enzymes driving the PPP occurs at an alkaline pHi, which is compatible with the cytoplasmic pH of cancer cells. Here, we outline each step of the PPP and discuss its possible correlation with cancer.

SUBMITTER: Alfarouk KO

PROVIDER: S-EPMC7407102 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH.

Alfarouk Khalid O KO Ahmed Samrein B M SBM Elliott Robert L RL Benoit Amanda A Alqahtani Saad S SS Ibrahim Muntaser E ME Bashir Adil H H AHH Alhoufie Sari T S STS Elhassan Gamal O GO Wales Christian C CC Schwartz Laurent H LH Ali Heyam S HS Ahmed Ahmed A Forde Patrick F PF Devesa Jesus J Cardone Rosa A RA Fais Stefano S Harguindey Salvador S Reshkin Stephan J SJ

Metabolites 20200711 7

The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the "Warburg Effect". However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced ...[more]

PMID: 32664469

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Project description:PurposeWe recently demonstrated that histone deacetylase (HDAC) inhibitors can "reprogram" differentiated triple-negative breast cancer cells to become quiescent stem-like cancer cells. We hypothesized that the metabolic state of such cells differs from that of their differentiated progeny.ResultsIn untreated cells, glucose uptake was higher in ALDH+ cells than in ALDH- cells (p = 0.01) but lactate production was not different; treating ALDH- or ALDH+ cells with VA or SAHA similarly increased glucose uptake without changing lactate production but upregulated G6PD, a rate-limiting enzyme in pentose phosphate pathway metabolism. NADPH production was higher in HDAC inhibitor-treated stem-like cells than in vehicle-treated cells (p < 0.05). Two G6PD inhibitors, 6-aminonicotinamide and dehydroepiandrosterone, decreased mammosphere formation efficiency and ALDH activity and 6-aminonicotinamide reduced the VA-induced increase in ALDH+ cells. Finally, patients expressing high G6PD mRNA had significantly worse overall survival (p < 0.001), and patients with high G6PD protein showed a similar trend towards worse disease-specific survival (p = 0.06).MethodsGlucose consumption, lactate and NADPH production, and reactive oxygen species generation were compared in aldehyde dehydrogenase (ALDH)-positive and -negative cells in the presence or absence of the HDAC inhibitors valproic acid (VA) or suberoylanilide hydroxamic acid (SAHA). Glucose-6-phosphate dehydrogenase (G6PD) expression was evaluated in a tissue microarray from 94 patients with node-positive invasive breast carcinoma and in two publically available databases and correlated with overall survival.ConclusionsEnergy metabolism in HDAC inhibitor-induced stem-like cancer cells differed sharply from that of differentiated cell types. HDAC inhibitor-induced dedifferentiation promoted metabolic reprogramming into the pentose phosphate pathway, which is targeted effectively by G6PD inhibition. These findings highlight a potential dual-therapy approach to targeting bulk differentiated cells with HDAC inhibitors and CSCs with G6PD inhibitors.

Dataset Information

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH.

Publications

The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH.

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