The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling

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Jieru Egeria Lin1, Peng Li, Adam Eugene Snook

  • 1Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Gastroenterology
|September 10, 2009
PubMed
Abstract

Insights

Loss of the Guanylyl Cyclase C (GUCY2C) receptor promotes intestinal tumorigenesis by activating AKT signaling. Restoring GUCY2C function or inhibiting AKT may offer new colorectal cancer therapies.

Area of Science:

  • Gastroenterology and Oncology
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Guanylyl Cyclase C (GUCY2C) is an intestinal receptor for guanylin and uroguanylin, crucial for intestinal homeostasis.
  • Loss of GUCY2C function disrupts intestinal homeostasis and promotes tumor development.
  • Investigating GUCY2C's role in intestinal cell proliferation, metabolism, signaling, and tumorigenesis is critical for understanding colorectal cancer.

Purpose of the Study:

  • To investigate the effects of GUCY2C loss on intestinal epithelial cell proliferation, metabolism, and signaling pathways.
  • To determine the role of AKT signaling in GUCY2C-mediated control of intestinal tumorigenesis.
  • To explore the therapeutic potential of targeting GUCY2C or its downstream pathways for colorectal cancer treatment.

Main Methods:

  • Comparative analysis of intestinal crypts and epithelial cell characteristics in Gucy2c(-/-) and wild-type mice.
  • Functional assays, including microscopy, immunoblotting, and gene expression profiling (microarray) to assess proliferation and metabolism.
  • Examination of AKT signaling pathways and validation using pharmacological and genetic disruption in Gucy2c(-/-) mice and human colon cancer cells.

Main Results:

  • Gucy2c(-/-) mice exhibited increased intestinal crypts, accelerated epithelial cell proliferation, enhanced glycolysis, and reduced oxidative phosphorylation, effects reversed by cGMP.
  • Activating GUCY2C in colon cancer cells reduced proliferation, DNA synthesis, and glycolysis, while increasing mitochondrial ATP production.
  • AKT signaling was hyperactivated in Gucy2c(-/-) intestines; inhibiting AKT reduced proliferation and tumorigenesis, while Gucy2c(-/-)Akt1(-/-) mice showed no increased tumor formation.

Conclusions:

  • GUCY2C acts as a tumor suppressor in the intestine by inhibiting AKT signaling, thereby controlling epithelial cell proliferation and metabolism.
  • The GUCY2C receptor and its peptide ligands represent potential therapeutic targets for colorectal cancer.
  • Targeting the GUCY2C pathway offers a promising strategy for novel anti-colorectal cancer therapies.

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