GUCY2C Opposes Premalignant Transformation in Intestine by Regulating PTEN-PI3K/AKT Signaling
An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developmental programs indelibly imprint restricted repertoires governing homeostasis, forming the substrate for lineage-dependent tumor induction by dysregulation of survival pathways. GUCY2C, the intestinal receptor for the paracrine hormones guanylin and uroguanylin whose early loss characterizes transformation, has emerged as a component of developmental programs organizing spatiotemporal patterning along the crypt-surface axis whose dysregulation promotes hyperproliferation and genetic instability underlying neoplasia. Here we identify GUCY2C as a reversible switch for lineage-dependent tumorigenesis whose disruption amplifies survival circuits essential for regenerative homeostasis and required for transformation. Elimination of GUCY2C in mice expands proliferating crypts, accelerating the cell cycle at the G1/S transition. Proliferative induction is coupled with altered metabolic programming, with an increase in aerobic glycolysis and a reciprocal reduction in mitochondrial biogenesis and oxidative phosphorylation, recapitulating the metabolic phenotype of human tumors. Conversely, GUCY2C signaling restores homeostatic circuits in colon cancer cells, decelerating the cell cycle and switching ATP production from glycolysis to mitochondrial metabolism, recapitulating normal enterocytes. Moreover, oral administration of the downstream mediator of GUCY2C signaling, cyclic GMP, reverses crypt hyperplasia and restores normal proliferative and metabolic programs in mice deficient in GUCY2C. Coordination of survival circuits by GUCY2C is orchestrated through the oncogene AKT, whose inhibition mimics, and activation eliminates, GUCY2C regulation of proliferation and metabolism. Modulation of AKT signaling by GUCY2C is, in part, mediated by the tumor suppressor, PTEN. Silencing PTEN eliminates GUCY2C regulation of AKT, proliferation and metabolism. Thus, disruption of developmentally restricted signaling by GUCY2C, reflecting loss of paracrine hormones, induces maladaptive survival pathways underlying crypt-surface homeostasis whose tissue-specific deregulation contributes to lineage dependency in intestinal tumorigenesis. With the role of guanylin and uroguanylin loss in transformation, the universal compensatory over-expression of GUCY2C by colorectal tumors offers a unique therapeutic opportunity for cancer prevention through oral hormone replacement therapy.
Lin, Jieru Egeria, "GUCY2C Opposes Premalignant Transformation in Intestine by Regulating PTEN-PI3K/AKT Signaling" (2010). ETD Collection for Thomas Jefferson University. AAI3551742.