Abstract
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.
Highlights
In many tumors, metabolism is strictly reprogrammed to generate energy and biomolecules required for uncontrolled growth that defines cancer [1,2]
Considering that microsatellite instability (MSI) is a marker of chemoresistance associated with improved survival compared with microsatellite-stable (MSS) colon cancers, we wanted to study the effects of glucose-6-phosphate dehydrogenase (G6PD) depletion in both genetic conditions as tumors respond differently to chemotherapy depending on this status [31,32]
We have observed that reducing the activity of G6PD by over 75% only decreased cells’ proliferation by over 20%, and it has been hypothesized that the demand for products of the G6PD reaction can be fulfilled by compensatory mechanisms such as the malic enzyme, isocitrate dehydrogenase or folate metabolism for NADPH production, by transketolase for ribose-5-phosphate synthesis, and by nutrient scavenging from the microenvironment
Summary
Metabolism is strictly reprogrammed to generate energy and biomolecules required for uncontrolled growth that defines cancer [1,2]. Even though glycolysis forms the backbone of central carbon metabolism, proliferating cells highly rely on the pentose phosphate pathway (PPP) in order to synthesize nucleotides for DNA replication and RNA synthesis. PPP provides an alternative route to glycolysis for the metabolism of glucose, and the percentage of glucose metabolized through PPP is known to vary from 5 to 30% depending on the tissue type [4]. 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.
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