A Warburg shakeup

Proc. Natl. Acad. Sci. USA 108, 18814–18819 (2011)

Credit: TOVE GRÖNROOS

The observation that cancer cells preferentially use glycolysis rather than oxidative phosphorylation—the Warburg effect—has substantially influenced thinking regarding cancer progression and potential therapeutics. However, a new study from Landor et al. demonstrates that increased glycolysis is not directly correlated with cancer progression and that metabolic flexibility is instead tied to aggressive cancer growth. The authors examined the relationship of Notch signaling to cellular metabolism by creating three engineered breast cancer cell lines with high, medium or low levels of Notch activity (N^high, N^medium and N^low, respectively). Implantation of these cells into mice caused initial tumor formation in all three lines, but after 8 weeks, N^high tumors had grown dramatically, whereas N^low tumors had regressed. Surprisingly, both N^high and N^low tumors showed increased glucose uptake and lactate production—hallmarks of increased glycolysis—compared to N^medium tumors. To explain these observations, the authors examined two cellular pathways that have previously been linked to glycolysis and mitochondrial function and discovered that Notch activation increased PI3K-AKT signaling, whereas decreased Notch activity inhibited mitochondrial function in a p53-dependent manner. The diminished mitochondrial function made N^low cells more susceptible to cell death upon glucose deprivation, whereas N^high cells were able to continue growing under the same circumstances. These results suggest that a deeper understanding of the link between metabolism and cellular signaling is needed to understand cancer development.