Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress

Abstract

BackgroundA variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis.ResultsAcidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes.ConclusionsAcidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific.

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

“…Consistent with the conflicting reports of the role of LGA in cancer, its expression can be upregulated both by the tumor suppressor p53 [62,118,119] and by the protooncoproteins c-Myc (reported in activated CD4 + T cells) and n-Myc [120,121].…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Acidic cancer cells switch from glycolysis to oxidative phosphorylation (Oxphos) to favour a generation of more bioenergetic molecules instead of biomass for cell division [27,39]. Metformin, a standard drug for diabetes, is a very efficient drug to kill acidic melanoma cells inhibiting their metabolic program [27].…”

Acidity of Microenvironment as a Further Driver of Tumor Metabolic Reprogramming

“…To sustain resistance to apoptosis, migration and distant dissemination, all energy-demanding processes, and in the absence of a sufficient glucose supply (already used by proliferating and hypoxic cells), acidic cells use alternative substrates such as lactate, free fatty acids and amino acids. Accordingly, acidosis increases both glutaminolysis and fatty acid β-oxidation in oxidative tumor cells contributing to the entry of metabolic intermediates into the TCA cycle and ATP generation [42]. Lactate also promotes glutamine uptake and metabolism in oxidative cancer cells [44].…”

“…Low pHe suppresses the hypoxia induced upregulation of PDK1, the effector of PDH inhibition and entry into mitochondrial respiration [40,41]. Breast cancer cells, grown in an acidic medium, also express a reduced glycolysis and lactate production and an increased respiratory metabolism [42]. More recently, we proved that both acidosis and lactic acidosis induce OxPhos metabolism in melanoma cells and, importantly, metformin, a mitochondrial complex I inhibitor, selectively targets and kills acidic cancer cells in a dose-dependent manner [35].…”