Yeast and Cancer: Common Mechanism Underlying Activation of Ras by Glycolytic Flux

Abstract

Ras proteins are small guanosine triphosphatases (GTPases), which function as on-off binary switches for diverse signaling pathways. Nearly 30% of human tumors have mutated forms of Ras. Both in the yeast Saccharomyces cerevisiae and in mammalian cells, Ras is an important regulator of cell proliferation. Mammalian Ras can functionally replace yeast Ras and hyperactive Ras oncogenes cause aberrant cell proliferation in yeast. Also the Ras regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), are homologous between yeast and mammalian cells. We used the tps1Δ mutant of the yeast S. cerevisiae as a tool to study Ras regulation. In the presence of glucose, this strain cannot grow due to a major metabolic deregulation causing hyperaccumulation of fructose-1,6-bisphosphate (Fru-1,6-bisP) and also hyperactivation of Ras leading to apoptosis. This led us to the finding that upon addition of glucose to wild type yeast cells, Fru-1,6-bisP promotes - in physiological concentrations - the activation of Ras through the GEF factor Cdc25. This activation may also be relevant in tumor biology because of the high glycolytic flux and higher concentrations of glycolytic intermediates present in cancer cells (Warburg effect). In vitro studies showed that Fru-1,6-bisP helps to increase the dissociation rate of the human K-Ras/SOS1 complex. Furthermore, we were able to show that glucose addition to glucose-deprived HEK293T and Hela Kyoto cells triggers rapid activation of Ras, as well as activation of its downstream targets MEK and ERK. Our results suggest that there may be a causal link between the high glycolytic activity and rapid cell proliferation of yeast and cancer cells in glucose medium through Fru-1,6-bisP activation of Ras. Support or Funding Information This work was supported by a PhD fellowship from the Agency for Innovation by Science and Technology (IWT-Flanders) to K.P., F.V.L., D.H., and W.V., by a post- doctoral F+-fellowship from the Research Fund of the KU Leuven to H.Q., and by grants from the Fund for Scientific Research—Flanders, Interuniversity Attraction Poles Net- work P6/14 and P7/40, and the Research Fund of the KU Leuven (Concerted Research Actions) to J.M.T., and a grant from the Belgian Foundation Against Cancer (FAF-F/ 2016/822) to V.J. Schematic overview of initial glucose metabolism in yeast and its connection to activation of the Ras-cAMP-PKA pathway. This pathway exerts major control over cell proliferation, fermentation rate, stress tolerance and developmental pathways in yeast. We show that Fru1,6bisP functions as activator of Ras by interacting with Cdc25 and that this connection between glycolysis and Ras is conserved between yeast and mammalian cells. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.