Metabolic reprogramming is a hallmark of cancer and is partially regulated by the PI3K/Akt pathway. Epithelial ovarian cancer (EOC) is one of the most common gynaecological cancers and dysregulated PI3K/Akt signalling is frequently detected. However, the metabolic impact remains unclear. Here, using the ID8 in vitro and in vivo model of EOC, I found that the deletion of Pten (i.e., the negative regulator of Akt) enhanced glycolysis, and modulated NAD+ metabolism and arginine synthesis.
The enhanced glycolysis induced by the hyperactive PI3K/Akt and Ras signalling may create a metabolic bottleneck by increasing the demand for NAD+ (a key glycolytic co-factor). Indeed, we previously showed NAD+ depletion by FK866, which inhibits NAD+ salvage synthesis, sensitized EOC cells to the PARP inhibitor Olaparib. Using a panel of EOC cells, I confirmed the higher sensitivity of the combination treatment in Ras/PI3K mutant cells. Mechanistically, higher DNA damage and oxidative stress were observed. The combination treatment improved median survival in the ID8 mouse model.
Lactate has been reported to fuel the TCA cycle in cancer cells. More recently, lactate acidosis uncouples glycolysis from the TCA cycle, which the lactate metabolon model can rationalize. Exogenous lactate forms a kinetically resolved pool from that derived from glycolysis and its derived pyruvate enters mitochondria before mixing with the glycolysis-derived pool. To test this hypothesis, I traced the relative contribution of glucose and exogenous lactate to citrate. A higher correlation was observed between labelling in citrate and pyruvate compared to exogenous lactate, which is inconsistent with the lactate metabolon model. Examining the roles of MCT1 and MCT4 (main lactate transporters) in this phenomenon I found that MCT1 was the major lactate transporter, and they were functionally redundant, which implies dual targeting may be necessary for therapeutic benefits.