Deletion of AC8 in glioma cells elevates oxidative phosphorylation by system-wide remodeling of the mitochondrial proteome.

The Warburg effect is the reprogramming of cancer cells towards glycolytic metabolism, likely producing and releasing lactate into the tumor microenvironment. This lactate has been suggested to partly drive tumor growth by signaling through the lactate receptor, GPR81. Thus, reprogramming cancer cells away from glycolytic activity may be beneficial for cancer treatment. Here, we show that deletion of ADCY8 (coding for adenylyl cyclase 8; AC8) employing the CRISPR-Cas9 technology in U87MG glioma cells, changes the proteome of these cells through a system-wide transformation in expression of mitochondrial proteins. These changes shift the metabolic balance towards oxidative phosphorylation, as shown by an increase in oxygen consumption, an elevation in tricarboxylic acid cycle flux, and a concomitant decrease in glycolytic flux. This metabolic shift is likely driven by the absence of AC8-mediated transcriptional regulation and may suggest that inhibition of AC8 activity could hold therapeutic potential in the treatment of cancer.