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Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression.

Abstract
Sporadic and non-hereditary mutations account for the majority of colorectal cancers (CRC). After the loss of adenomatous polyposis coli (APC) function and activation of the β-catenin/LEF signaling pathway, activating mutations in Kras are major drivers of sporadic CRC. Preventing the outgrowth of cells that develop sporadic mutations will decrease CRC. Resveratrol, a naturally occurring polyphenolic compound has anti-inflammatory, anti-oxidant and anti-cancer activities. We used a genetically engineered mouse model for sporadic CRC where the APC locus is knocked out and Kras is activated specifically in the distal colon to determine the effects of resveratrol on preventing and treating CRC. Feeding mice a diet supplemented with 150 or 300 ppm resveratrol (105 and 210mg daily human equivalent dose, respectively) before tumors were visible by colonoscopy resulted in a 60% inhibition of tumor production. In the 40% of mice that did develop tumors Kras expression was lost in the tumors. In a therapeutic assay where tumors were allowed to develop prior to treatment, feeding tumor bearing mice with resveratrol resulted in a complete remission in 33% of the mice and a 97% decrease in tumor size in the remaining mice. Analysis of miRNA expression in non-tumoral and tumoral colonic tissue of resveratrol treated mice showed an increased expression of miR-96, a miRNA previously shown to regulate Kras translation. These data indicate that resveratrol can prevent the formation and growth of colorectal tumors by downregulating Kras expression.
AuthorsShakir M Saud, Weidong Li, Nicole L Morris, Matthias S Matter, Nancy H Colburn, Young S Kim, Matthew R Young
JournalCarcinogenesis (Carcinogenesis) Vol. 35 Issue 12 Pg. 2778-86 (Dec 2014) ISSN: 1460-2180 [Electronic] England
PMID25280562 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
CopyrightPublished by Oxford University Press 2014.
Chemical References
  • Adenomatous Polyposis Coli Protein
  • Anticarcinogenic Agents
  • RNA, Messenger
  • Stilbenes
  • Kras2 protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • resveratrol
Topics
  • Adenomatous Polyposis Coli Protein (physiology)
  • Animals
  • Anticarcinogenic Agents (therapeutic use)
  • Blotting, Western
  • Cell Proliferation (drug effects)
  • Cell Transformation, Neoplastic (drug effects, genetics, pathology)
  • Colorectal Neoplasms (etiology, pathology, prevention & control)
  • Disease Models, Animal
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Mutation (genetics)
  • Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics)
  • RNA, Messenger (genetics)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stilbenes (therapeutic use)
  • Tumor Cells, Cultured

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