title: Carnosol inhibits beta-catenin tyrosine phosphorylation and prevents adenoma formation in the C57BL/6J/Min/+ (Min/+) mouse.
abstract: Carnosol, a constituent of the herb, rosemary, has shown beneficial medicinal and antitumor effects. Using the C57BL/6J/Min/+ (Min/+) mouse, a model of colonic tumorigenesis, we found that dietary administration of 0.1% carnosol decreased intestinal tumor multiplicity by 46%. Previous studies showed that tumor formation in the Min/+ mouse was associated with alterations in the adherens junctions, including an increased expression of tyrosine-phosphorylated beta-catenin, dissociation of beta-catenin from E-cadherin, and strongly reduced amounts of E-cadherin located at lateral plasma membranes of histologically normal enterocytes. Here, we confirm these findings and show that treatment of Min/+ intestinal tissue with carnosol restored both E-cadherin and beta-catenin to these enterocyte membranes, yielding a phenotype similar to that of the Apc(+/+) wild-type (WT) littermate. Moreover, treatment of WT intestine with the phosphatase inhibitor, pervanadate, removed E-cadherin and beta-catenin from the lateral membranes of enterocytes, mimicking the appearance of the Min/+ tissue. Pretreatment of WT tissue with carnosol inhibited the pervanadate-inducible expression of tyrosine-phosphorylated beta-catenin. Thus, the Apc(Min) allele produces adhesion defects that involve up-regulated expression of tyrosine-phosphorylated proteins, including beta-catenin. Moreover, these data suggest that carnosol prevents Apc-associated intestinal tumorigenesis, potentially via its ability to enhance E-cadherin-mediated adhesion and suppress beta-catenin tyrosine phosphorylation.
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Moran
authors.forename: Adelaide M
authors.initials: AM
authors.lastname: Carothers
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.forename: Mark
authors.initials: M
authors.lastname: Redston
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000236:Adenoma / Q000517:prevention & control*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000517:prevention & control*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D027542:Rosmarinus / Q000737:chemistry; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051176:beta Catenin
chemical_list: D045784:Abietanes; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D010616:Phenanthrenes; D015534:Trans-Activators; D051176:beta Catenin; C076715:pervanadate; D014638:Vanadates; D014443:Tyrosine; C068623:carnosol