Proton sensing GPCR’s: The missing link to Warburg’s oncogenic legacy?

A century after Otto Warburg's seminal discovery of aerobic glycolysis in cancer cells, a phenomenon dubbed the "Warburg effect", the mechanistic links between this metabolic rewiring and tumorigenesis remain elusive. Warburg postulated that this enhanced glucose fermentation to lactate, even in the presence of oxygen, stemmed from an "irreversible respiratory injury" intrinsic to cancer cells. While oxidative phosphorylation yields higher ATP, the Warburg effect paradoxically persists, suggesting that the excess lactate and acid production are worth the deficit. Since Warburg's discovery, it has been demonstrated that the acidic tumor microenvironment activates a myriad of pro-oncogenic phenotypes ranging from therapeutic resistance to immune escape. Here we propose that proton-sensing G-protein-coupled receptors (GPCRs) act as crucial heirs to Warburg's findings by transducing the acid signal from elevated glycolytic lactate into pro-oncogenic signals. The increased lactate production characteristic of the Warburg effect causes extracellular acidification. This acidic tumor microenvironment can activate proton-sensing GPCRs like GPR68, a proton-sensing receptor shown to stimulate proliferation, migration, and survival pathways in cancer cells. Such pH sensing is accomplished through protonation of key residues such as histidine, which causes a conformational change to activate various downstream signaling cascades including the MAPK, PI3K/Akt, Rho, and β-arrestin pathways implicated in tumor progression and therapeutic resistance. By coupling Warburg's "respiratory injury" to potent mitogenic signaling, proton-sensing GPCRs like GPR68 may unveil a longstanding mystery - why forgo efficient ATP generation? As heirs to Warburg's iconic metabolic observations, these proton sensors could represent novel therapeutic targets to disrupt the synergy between the Warburg effect and oncogenic signaling.