Abstract
Resveratrol (RES), a polyphenol found in natural foods, displays anti-oxidant, anti-inflammatory and anti-proliferative properties potentially beneficial in cancers, in particular in the prevention of tumor growth. However, the rapid metabolism of resveratrol strongly limits its bioavailability. The molecular mechanisms sustaining the potential biological activity of low doses of resveratrol has not been extensively studied and, thus, needs better characterization. Here, we show that resveratrol (10 µM, 48 hr) induces both a cell growth arrest and a metabolic reprogramming in colon cancer cells. Resveratrol modifies the lipidomic profile, increases oxidative capacities and decreases glycolysis, in association with a decreased pentose phosphate activity and an increased ATP production. Resveratrol targets the pyruvate dehydrogenase (PDH) complex, a key mitochondrial gatekeeper of energy metabolism, leading to an enhanced PDH activity. Calcium chelation, as well as the blockade of the mitochondrial calcium uniport, prevents the resveratrol-induced augmentation in oxidative capacities and the increased PDH activity suggesting that calcium might play a role in the metabolic shift. We further demonstrate that the inhibition of the CamKKB or the downstream AMPK pathway partly abolished the resveratrol-induced increase of glucose oxidation. This suggests that resveratrol might improve the oxidative capacities of cancer cells through the CamKKB/AMPK pathway.
Highlights
Cancer cells have energetic needs that differ from those of the tissues from which they are derived and, they modify their use of metabolites to meet these requirements
Resveratrol was found to negatively regulate some of the proteins and enzymes involved in glucose metabolism such as the glucose transporter GLUT18, phosphofructokinase (PFK1)[4, 6], hexokinase 2 (HK2), phosphoglycerate mutase (PGAM)[6], glucose 6 phosphate dehydrogenase (G6PD), transketolase (TKT)[9] and (PKM2)[7]
We suggest that the pyruvate dehydrogenase (PDH) complex, a key enzyme that controls the fate of pyruvate, is a new metabolic target for resveratrol
Summary
Cancer cells have energetic needs that differ from those of the tissues from which they are derived and, they modify their use of metabolites to meet these requirements. Most cancer cells exhibit an altered metabolism that is characterized by increased glycolysis and lactate production regardless of the availability of oxygen This phenomenon is known as the Warburg effect[1] and it constitutes a hallmark of cancer metabolism. The PI3K signaling pathway has been reported to be involved in the resveratrol-induced inhibition of glycolysis associated with cell growth arrest in B cell lymphoma[6], and in breast and colon cancer cells[5, 8]. They emphasize that enzymes which are involved in the control of the fate of glucose and its metabolites are relevant targets of the polyphenolic compound
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