Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin

Cancer Res. 2013 Sep 1;73(17):5473-84. doi: 10.1158/0008-5472.CAN-13-0525. Epub 2013 Jul 1.

Abstract

Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS-induced oncogenic c-Src activation and β-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and β-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Azoxymethane / toxicity
  • Blotting, Western
  • CSK Tyrosine-Protein Kinase
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / prevention & control*
  • Dextran Sulfate
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Phytotherapy*
  • Plant Extracts / pharmacology*
  • Protein Transport
  • Quercetin / analogs & derivatives*
  • Quercetin / pharmacology
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • beta Catenin / genetics
  • beta Catenin / metabolism*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*

Substances

  • Plant Extracts
  • RNA, Messenger
  • RNA, Small Interfering
  • beta Catenin
  • 3-methylquercetin
  • Dextran Sulfate
  • Quercetin
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Azoxymethane