Carcinogenesis Advance Access published online on December 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl232
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Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha-RAS transformed human colon cells.
1 Laboratory of Signal Mediated Gene Expression, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vas. Konstantinou Avenue, Athens 11635, Greece
2 Department of Pathology, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan
3 Current address: Regulon SA, 7, Gregoriou Afxentiou, 17455 Athens, Greece
4 Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 22 Papakyriazi Street, Larisa 41222, Greece
Correspondence to: Alexander Pintzas, Tel: 30 210 7273753, Fax: 30 210 7273745, apint{at}eie.gr
Several food polyphenols act as chemopreventers by reducing the incidence of many types of cancer, especially in colon epithelia. In this study, we have investigated whether the flavonoid quercetin can modulate cell proliferation and survival by targeting key molecules and/or biological processes responsible for tumor cell properties. The effect of quercetin on the expression of Ras oncoproteins was specifically studied using systems of either constitutive or conditional expression of oncogenic RAS in human epithelial cells. Our findings suggest that quercetin inhibits cell viability as well as cancer cell properties like anchorage independent growth. These findings were further supported at the molecular level, since quercetin treatment resulted in a preferential reduction of Ras protein levels in cell lines expressing oncogenic Ras proteins. Notably, in cells that only express wild-type Ras or in those where the oncogenic Ras allele was knocked out, quercetin had no evident effects upon Ras levels. We have shown that quercetin drastically reduces half-life of oncogenic Ras but has no effect when the cells are treated with a proteasome inhibitor. Moreover, in Ha-RAS transformed cells quercetin induces autophagic processes. Since quercetin downregulates the levels of oncogenic Ras in cancer cells, we propose that this flavonoid could act as a chemopreventive agent for cancers with frequent mutations of RAS genes.
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