The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy

Abstract

Extracellular tumor acidosis largely results from an exacerbated glycolytic flux in cancer and cancerassociated cells. Conversely, little is known about how tumor cells adapt their metabolism to acidosis. Here, we demonstrate that long-term exposure of cancer cells to acidic pH leads to a metabolic reprogramming toward glutamine metabolism. This switch is triggered by the need to reduce the production of protons from glycolysis and further maintained by the NAD þ -dependent increase in SIRT1 deacetylase activity to ensure intracellular pH homeostasis. A consecutive increase in HIF2a activity promotes the expression of various transporters and enzymes supporting the reductive and oxidative glutamine metabolism, whereas a reduction in functional HIF1a expression consolidates the inhibition of glycolysis. Finally, in vitro and in vivo experiments document that acidosis accounts for a net increase in tumor sensitivity to inhibitors of SIRT1 and glutaminase GLS1. These findings highlight the influence that tumor acidosis and metabolism exert on each other.

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

“…Involvement of PHD inhibition for lactate-induced HIF-1a and HIF-2a stabilization does not exclude additional effects of lactate on the cellular redox status, as lactate oxidation to pyruvate (the lactate dehydrogenase 1 reaction) increases the NADH/NAD C ratio and pyruvate has antioxidant properties. 49,50 Considering that cancer cells chronically adapted to extracellular acidity activate HIF-2a and become addicted to glutamine, 51 the contribution of protons cotransported with lactate by MCT1 certainly deserves further consideration.…”

“…A previously disclosed protocol 51 c-Myc activity assays c-Myc activity was measured using the dual luciferase kit from Promega with pBV-Luc wt MBS1-4 (Addgene) as reporter of c-Myc activity and pRL Renilla Luciferase (Promega) as internal control. Cells were co-transfected using lipofectamine RNAiMax (Life Technologies).…”

“…51 SiHa cells (500,000/well) were seeded in poly-L-lysine-coated 24-well plates. After overnight incubation, culture medium was replaced by 1 ml DMEM § 10 mM sodium lactate, and cells were incubated for 6-h.…”

Manipulating Angiogenesis by Targeting Endothelial Metabolism: Hitting the Engine Rather than the Drivers—A New Perspective?

“…Last, it will be of interest to examine whether tumor acidosis affects tumor EC metabolism and signaling because of acetylation events, as recently shown in cancer cells (Corbet et al, 2014). In addition to global changes in the acetylation profile, a specific increase in Sirtuin 1-dependent deacetylation events in acidic regions could lead to changes in angiogenesis-limiting signals.…”

Sirtuins and the Metabolic Hurdles in Cancer

“…A recent study shows SIRT1 promotes reductive carboxylation (Figure 3B)[135]. In diverse cancer cell lines, prolonged acidosis (pH 6.5), which mimics extensive lactate production, upregulates genes important for reverse TCA cycle flux in a SIRT1-dependent manner.…”