Mitochondrial DNA content reduction induces aerobic glycolysis and reversible resistance to drug-induced apoptosis in SW480 colorectal cancer cells

Abstract

Mutations and reductions in mitochondrial DNA (mtDNA), which are frequent in human tumors, may contribute to enhancing their malignant phenotypes. However, the effects of mtDNA abnormalities in colorectal cancer remain largely unknown. In this study, mtDNA-reduced cell model was established by partial depletion of mtDNA in SW480 cells and the effects of mtDNA reduction in colorectal cancer cells were investigated. We found that mtDNA-reduced cells had enhanced glucose uptake and generated markedly higher level of lactate. These changes were accompanied by only a slight reduction in ATP production compared with the parent cells. Furthermore, the activity of the glycolytic enzymes, hexokinase (HK) and phosphofructokinase (PFK), was increased in mtDNA-reduced cells. These results suggested a switch to aerobic glycolysis in mtDNA-reduced cells, which helped the cells to gain a survival advantage. Notably, when mtDNA content was restored, metabolism returned to normal. In addition, the mtDNA-reduced cells were highly resistant to 5-fluorouracil- and oxaliplatin-induced apoptosis and this drug resistance was reversible following recovery of the mtDNA content. We also found that the Akt/mTOR pathway was activated in the mtDNA-reduced cells. This pathway might play a significant role in drug resistance in the mtDNA-reduced cells as drug susceptibility was restored when this pathway was inhibited. Taken together, our results supported the notion that mtDNA reduction induced aerobic glycolysis and a reversible apoptosis-resistant phenotype in SW480 cells, and that the Akt/mTOR pathway might be involved in the drugs-induced apoptosis resistance.