Glucose-6-phosphate dehydrogenase and transketolase modulate breast cancer cell metabolic reprogramming and correlate with poor patient outcome.

Adrián Benito,Silvia Marin,Véronique Noé,Carlos J Ciudad,Marta Cascante,Ibrahim H Polat

doi:10.18632/oncotarget.21601

Abstract

The pentose phosphate pathway is a fundamental metabolic pathway that provides cells with ribose and NADPH required for anabolic reactions — synthesis of nucleotides and fatty acids — and maintenance of intracellular redox homeostasis. It plays a key role in tumor metabolic reprogramming and has been reported to be deregulated in different types of tumors. Herein, we silenced the most important enzymes of this pathway — glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) — in the human breast cancer cell line MCF7. We demonstrated that inhibition of G6PD, the oxidative branch-controlling enzyme, reduced proliferation, cell survival and increased oxidative stress. At the metabolic level, silencing of both enzymes reduced ribose synthesis. G6PD silencing in particular, augmented the glycolytic flux, reduced lipid synthesis and increased glutamine uptake, whereas silencing of TKT reduced the glycolytic flux. Importantly, we showed using breast cancer patient datasets that expression of both enzymes is positively correlated and that high expression levels of G6PD and TKT are associated with decreased overall and relapse-free survival. Altogether, our results suggest that this metabolic pathway could be subjected to therapeutic intervention to treat breast tumors and warrant further investigation.

Highlights

Cancer cells need to reprogram their metabolism to fulfill specific metabolic requirements and to achieve a fully malignant phenotype [1, 2]
Since phosphate pathway (PPP) is an anabolic pathway that plays a fundamental role in cell growth, we examined the role of TKT and glucose-6-phosphate dehydrogenase (G6PD) in proliferation and survival by performing proliferation experiments in combination with propidium iodide (PI) staining
We demonstrated that silencing of G6PD increases glycolytic flux, glutamine consumption and ROS levels, and decreases glucose-derived synthesis of acetyl-CoA, palmitate and stearate

Summary

Introduction

Cancer cells need to reprogram their metabolism to fulfill specific metabolic requirements and to achieve a fully malignant phenotype [1, 2]. The so-called tumor metabolic reprogramming is aimed to meet the bioenergetics demands of cancer cells, providing them with precursors for the synthesis of macromolecules and maintaining redox homeostasis [3]. One of the most important metabolic pathways that participate in these processes is the pentose phosphate pathway (PPP), which synthesizes the nucleotide precursor ribose-5-phosphate and produces the reduced form of the nicotinamide adenine dinucleotide phosphate (NADPH), an essential cofactor required for the synthesis of lipids and the maintenance of the antioxidant systems, such as the reduced glutathione pool. The pentose phosphate pathway is divided into the oxidative and the non-oxidative branches. The oxidative branch (ox-PPP) catalyzes the irreversible transformation of glucose-6-phosphate (G6P) into ribulose-5-phosphate (Ri5P) with the subsequent production of NADPH and CO2. The non-oxidative branch (nonox-PPP) is a reversible pathway that interconverts glyceradehyde-3-

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