Guanylyl Cyclase C is the metabolic switch for the Warburg effect in colorectal cancer Free

LB-369

The Warburg effect, a shift from oxidative phosphorylation to glycolysis, is a fundamental characteristic of neoplasia, including in the colon and rectum, providing a competitive advantage to tumor cells. In colorectal carcinogenesis the most commonly lost gene products include guanylin and uroguanylin, which are ligands for GCC, although the role of this signaling system in tumorigenesis remains obscure. Here, we explored the role of GCC in orchestrating the metabolic progression of intestinal cells along the crypt-villus axis and the corruption of this mechanism in metabolic remodeling characterizing colorectal cancer. Ligand activation of GCC in intestinal cells induced the transcription factors PGC1α, mtTFA, and NRF1 which mediated mitochondrial biogenesis, increasing the content of mitochondrial genome, protein, and structural elements. In addition, GCC signaling reciprocally regulated glycolysis by reducing key regulatory enzymes including Glut 1, hexokinase, phosphofructokinase, and pyruvate kinase. Further, activation of GCC reverted the metabolic phenotype of colon cancer cells to that of normal intestinal cells, characterized by a shift from glycolysis to oxidative phosphorylation, with an increase in oxygen consumption and intracellular ATP, and a concomitant decrease in lactate production. Conversely, eliminating GCC in intestinal cells in mice (GCC^-/-) produced a metabolic phenotype reminiscent of colon cancer. GCC^-/- mice developed mitochondrial insufficiency and reciprocal over-expression of glycolytic components compared to GCC^+/+ mice. Indeed, deletion of GCC eliminated the coordinated progression of the metabolic phenotype from glycolysis to oxidative phosphorylation characterizing the transition from proliferation to differentiation along the crypt-villus axis. Moreover, normal intestinal cells in GCC^-/- mice exhibited a metabolic shift characterizing tumor cells, with a decrease in mitochondria-associated activities and an increase in lactate production. Together, these observations demonstrate a previously unappreciated role for GCC in coordinating glycolytic and oxidative metabolism along the crypt-villus axis in intestine. The invariant disruption in guanylin and uroguanylin expression in carcinogenesis and the ability of GCC ligands to revert the metabolic phenotype of colon cancer cells suggest that dysregulation of GCC signaling reflecting loss of ligand expression mediates metabolic remodeling to the Warburg phenotype promoting tumorigenesis. In that context, the uniform over-expression of GCC by colon tumors presents a novel therapeutic opportunity, underscoring the potential of oral administration of GCC ligands for targeted prevention of colorectal cancer.