Inhibition of pyruvate dehydrogenase kinase activity promotes apoptosis in colorectal cancer cells
Session type: Parallel sessions
The Leeds Teaching Hospitals NHS Trust, University of Leeds, Leeds, West Yorkshire, UK
Proffered paper presentation
Cancer cells are highly dependent on glycolysis, the so-called Warburg effect, which provides them with a competitive edge over normal cells. This study aimed to determine if switching metabolism from glycolysis towards glucose oxidation induces apoptosis preferentially in colorectal cancer cells over normal cells, and to examine the underlying mechanisms.
Cell lines were treated with dichloroacetate, a non-specific inhibitor of pyruvate dehydrogenase kinase (PDK) that promotes mitochondrial respiration. Assays were performed to determine cell viability, apoptosis, cell-cycle profiles and metabolic effects.
Treatment with dichloroacetate reduced cell viability in a dose-dependent fashion. 20 mM dichloroacetate did not significantly reduce viability of the non-cancerous 293 cells, but caused a 30% decrease in cancer cell viability. The decreased viability was due to a significant increase in proportion of apoptotic cells and cells arrested in G2. The largest apoptotic effect was evident in the metastatic LoVo cells. The mean percentage of apoptotic cells with no dichloroacetate was 2 (95%CI: 0.9 to 3.1) compared to 23 (95%CI: 11.5 to 34.6) with dichloroacetate. 293 cells were unaffected by dichloroacetate treatment: 0.6 (95%CI: -0.2 to 1.4) vs. 0.9 (95%CI: -0.1 to 1.7). Dichloroacetate produced an 8-fold increase in the proportion of cancer cells in G2. To analyse the alterations in metabolism, lactate levels and intrinsic mitochondrial membrane potential (∆Ym) were measured. Dichloroacetate caused a 70% reduction in lactate levels in both LoVo and 293 cells, suggesting that it attenuates glycolysis. Dichloroacetate decreased ∆Ym in all cancer cells, but not in 293 cells, indicating that it facilitates glucose oxidation in cancer cells.
PDK inhibition with dichloroacetate induces apoptosis in colorectal cancer cells, possibly via the mitochondrial pathway. Further research to downregulate the activity of the specific isoforms of PDK that are upregulated in cancer is warranted.