Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin
Menée in vitro et à l'aide d'un modèle murin traité par l'azoxyméthane (un agent carcinogène) puis exposé au dextran sulfate de sodium (un irritant colique), cette étude montre que l'isorhamnétine, un composé flavonoïde d'origine végétale, a un effet chimiopréventif sur la carcinogenèse du côlon en inhibant l'activité oncogène de Src et la translocation nucléaire de la
Analysis of the Polyp Prevention Trial showed an association between isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism of isorhamnetin's chemoprotective effects remains unclear. Here we demonstrate that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane (AOM) 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. Magnetic resonance imaging, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than 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 RNAi knock down 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.