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• W2227571872 abstract "LB-279 Guanylyl cyclase C (GCC), the intestinal receptor for the paracrine hormones guanylin and uroguanylin whose early loss is universally associated with initiation of colorectal cancer, has emerged as a tumor suppressor whose dysregulation promotes proliferation and produces genomic instability underlying intestinal neoplasia. Beyond corruption of replicative and genomic integrity, reprogramming of metabolic circuits confers a survival advantage to cancer cells globally licensing tumor initiation and progression in all tissues. Here, we show that GCC is a systems integrator, coordinating glycolytic and oxidative metabolism with proliferation underlying normal regenerative homeostasis along the crypt-surface axis, and opposing tumorigenesis, in intestine. Eliminating GCC signaling in mice expands the proliferating crypt compartment, accelerating the cell cycle by inducing critical mediators including cyclin D and phosphorylated Rb. Replicative induction is coupled with an increase in glucose transport and the glycolytic machinery and a reciprocal reduction in mitochondrial biogenesis and oxidative phosphorylation, recapitulating the neoplastic metabolic phenotype defining a tumorigenic niche. Conversely, GCC signaling reverts neoplastic proliferative and metabolic programming in human colon cancer cells, decelerating the cell cycle and switching from glycolytic to mitochondrial ATP production, reminiscent of normal enterocytes. Coordination of proliferative and metabolic circuits in vitro and in vivo is orchestrated by GCC through suppression of signaling by AKT, a key mediator of neoplastic transformation. Pharmacologic and genetic inhibition of AKT signaling mimics, while constitutive activation eliminates, the ability of GCC to regulate proliferative and metabolic programming in human colon cancer cells. GCC suppresses AKT signaling by inducing a cyclic GMP-dependent activation of the phosphatase and tensin homolog (PTEN), an antagonist of phosphoinositide 3 (PI3)-kinase signaling central to activating AKT. In the context of the universal loss of guanylin and uroguanylin early in neoplastic transformation, these observations reveal for the first time the molecular mechanisms coordinating reprogramming of replicative and metabolic circuits underlying tumor initiation in intestine. With hormone insufficiency initiating signal dysregulation reinforcing intestinal transformation, pervasive over-expression of GCC by human colorectal tumors offers a unique therapeutic opportunity for cancer prevention and regression through oral ligand replacement therapy." @default.
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• W2227571872 date "2008-05-01" @default.
• W2227571872 modified "2023-09-23" @default.
• W2227571872 title "Guanylyl cyclase C integrates metabolic and proliferative programming opposing intestinal tumorigenesis through AKT" @default.
• W2227571872 hasPublicationYear "2008" @default.
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