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Carnosol Inhibits ß-Catenin Tyrosine Phosphorylation and Prevents Adenoma Formation in the C57BL/6J/Min/+ (Min/+) Mouse

¹ Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University and ² Strang Cancer Prevention Center, New York, New York and Departments of ³ Surgery and ⁴ Pathology, Brigham and Women's Hospital, Boston, Massachusetts

Requests for reprints: Monica M. Bertagnolli, Department of Surgery, Brigham and Women's Hospital 75 Francis Street, Boston, MA 02115. Phone: 617-732-8910; Fax: 617-582-6177; E-mail: mbertagnolli{at}partners.org.

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 ß-catenin, dissociation of ß-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 ß-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 ß-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 ß-catenin. Thus, the Apc^Min allele produces adhesion defects that involve up-regulated expression of tyrosine-phosphorylated proteins, including ß-catenin. Moreover, these data suggest that carnosol prevents Apc-associated intestinal tumorigenesis, potentially via its ability to enhance E-cadherin-mediated adhesion and suppress ß-catenin tyrosine phosphorylation.

Key Words: Gastrointestinal cancers: colorectal • Animal models of cancer • Biological and biochemical mechanisms in prevention • Diet and cancer

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