Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Guanylyl cyclase C (GC‐C), a transmembrane receptor for bacterial heat‐stable enterotoxin and the mammalian peptides guanylin and uroguanylin, mediates intestinal ion secretion and affects intestinal cell growth via cyclic GMP signaling. In intestinal tumors, GC‐C expression is maintained while guanylin and uroguanylin expression is lost, suggesting a role for GC‐C activation in tumor formation or growth. We show by in situ hybridization that GC‐C expression is retained in adenomas from multiple intestinal neoplasia (ApcMin/+) mice. In order to determine the in vivo role of GC‐C in intestinal tumorigenesis, we generated ApcMin/+ mice homozygous for a targeted deletion of the gene encoding GC‐C and hypothesized that these mice would have increased tumor multiplicity and size compared to wild‐type ApcMin/+ mice on the same genetic background. In contrast, the absence of GC‐C resulted in a reduction of median polyp number by 55%. There was no change in the median diameter of polyps, suggesting no effect on tumor growth. Somatic loss of the wild‐type Apc allele, an initiating event in intestinal tumorigenesis, also occurred in polyps from GC‐C‐deficient ApcMin/+ mice. We have found increased levels of apoptosis as well as increased caspase‐3 and caspase‐7 gene expression in the intestines of GC‐C‐deficient ApcMin/+ mice compared with ApcMin/+ mice. We propose that these alterations are a possible compensatory mechanism by which loss of GC‐C signaling also affects tumorigenesis. Published 2005 Wiley‐Liss, Inc.

[1]  G. Piazza,et al.  Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells. , 2003, Molecular cancer therapeutics.

[2]  I. Yang,et al.  Regulation of caspase expression and apoptosis by adenomatous polyposis coli. , 2003, Cancer research.

[3]  T. Tsuzuki,et al.  The role of P-glycoprotein in intestinal tumorigenesis: disruption of mdr1a suppresses polyp formation in ApcMin/+ mice , 2003 .

[4]  A. E. Alekseev,et al.  Bacterial enterotoxins are associated with resistance to colon cancer , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Ahnen,et al.  Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase 1/2 and Bad in human colon cancer cells. , 2003, Cancer research.

[6]  Christopher F. Martin,et al.  Nonsteroidal anti-inflammatory drugs, apoptosis, and colorectal adenomas. , 2002, Gastroenterology.

[7]  Ming Chen,et al.  Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation. , 2002, Biochemical pharmacology.

[8]  V. Yang APC as a checkpoint gene: the beginning or the end? , 2002, Gastroenterology.

[9]  N. Schuster,et al.  The role of transforming growth factor beta-2, beta-3 in mediating apoptosis in the murine intestinal mucosa. , 2002, Gastroenterology.

[10]  M. Pignatelli,et al.  β-catenin - A linchpin in colorectal carcinogenesis? , 2002 .

[11]  M. Kay Washington,et al.  Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Li Liu,et al.  Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. , 2001, The Journal of pharmacology and experimental therapeutics.

[13]  P. Sen,et al.  STa-induced translocation of protein kinase C from cytosol to membrane in rat enterocytes. , 2001, FEMS microbiology letters.

[14]  S. Waldman,et al.  Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  I. Weinstein,et al.  Protein Kinase G Activates the JNK1 Pathway via Phosphorylation of MEKK1* , 2001, The Journal of Biological Chemistry.

[16]  D. Ahnen,et al.  Inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and induction of apoptosis by sulindac metabolites. , 2001, Cancer research.

[17]  E. Mann,et al.  Effect of E. coli heat-stable enterotoxin on colonic transport in guanylyl cyclase C receptor-deficient mice. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[18]  K. Shailubhai,et al.  Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP. , 2000, Cancer research.

[19]  G. Piazza,et al.  Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. , 2000, Cancer research.

[20]  M. Cohen,et al.  Expression of guanylin is downregulated in mouse and human intestinal adenomas. , 2000, Biochemical and biophysical research communications.

[21]  S. Guggino,et al.  Cyclic nucleotide-gated cation channels mediate sodium and calcium influx in rat colon. , 2000, American journal of physiology. Cell physiology.

[22]  Alan R. Saltiel,et al.  Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo , 1999, Nature Medicine.

[23]  C. Albanese,et al.  The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Kucherlapati,et al.  Genotype-phenotype correlation in murine Apc mutation: differences in enterocyte migration and response to sulindac. , 1999, Cancer research.

[25]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[26]  M. Chakrabarti,et al.  Rise of intracellular free calcium levels with activation of inositol triphosphate in a human colonic carcinoma cell line (COLO 205) by heat-stable enterotoxin of Escherichia coli. , 1998, Biochimica et biophysica acta.

[27]  E. Mann,et al.  Mice lacking the guanylyl cyclase C receptor are resistant to STa-induced intestinal secretion. , 1997, Biochemical and biophysical research communications.

[28]  M. Kuhn,et al.  Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxin-resistant mice. , 1997, The Journal of clinical investigation.

[29]  M. Cohen,et al.  Uroguanylin and guanylin: distinct but overlapping patterns of messenger RNA expression in mouse intestine. , 1997, Gastroenterology.

[30]  S J Parkinson,et al.  Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Witte,et al.  The guanylin/STa receptor is expressed in crypts and apical epithelium throughout the mouse intestine. , 1996, Biochemical and biophysical research communications.

[32]  S. Waldman,et al.  Escherichia coli heat-stable enterotoxin receptors , 1996, Diseases of the colon and rectum.

[33]  P. Pasricha,et al.  The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. , 1995, Gastroenterology.

[34]  A. Chaudhuri,et al.  Evidence for stimulation of the inositol triphosphate-Ca2+ signalling system in rat enterocytes by heat stable enterotoxin of Escherichia coli. , 1995, Biochimica et biophysica acta.

[35]  A. Moser,et al.  Loss of Apc+ in intestinal adenomas from Min mice. , 1994, Cancer research.

[36]  S. Eber,et al.  Distribution of heat-stable enterotoxin/guanylin receptors in the intestinal tract of man and other mammals. , 1994, Journal of anatomy.

[37]  E. Lander,et al.  Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse , 1993, Cell.

[38]  H. Pitot,et al.  A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. , 1990, Science.

[39]  K. Barrett,et al.  A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[40]  A. Vaandrager Structure and function of the heat-stable enterotoxin receptor/guanylyl cyclase C , 2004, Molecular and Cellular Biochemistry.

[41]  L. Siracusa,et al.  Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. , 2002, Genome research.

[42]  M. Pignatelli,et al.  Beta-catenin--a linchpin in colorectal carcinogenesis? , 2002, The American journal of pathology.

[43]  G. Piazza,et al.  Sulindac sulfone induced regression of rectal polyps in patients with familial adenomatous polyposis. , 1999, Advances in experimental medicine and biology.

[44]  M. Cohen,et al.  Guanylin mRNA expression in human intestine and colorectal adenocarcinoma. , 1998, Laboratory investigation; a journal of technical methods and pathology.