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Carcinogenesis Advance Access originally published online on December 5, 2006
Carcinogenesis 2007 28(5):1021-1031; doi:10.1093/carcin/bgl232
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha-RAS-transformed human colon cells

Faiy H. Psahoulia1,3, Sophy Moumtzi1, Michael L. Roberts1,4, Takehiko Sasazuki2, Senji Shirasawa2 and Alexander Pintzas1,*

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 Department of Medicine, School of Health Sciences, University of Thessaly, 22 Papakyriazi Street, Larisa 41222, Greece
4 Present address: Regulon SA, 7, Gregoriou Afxentiou, Athens 17455, Greece

* To whom correspondence should be addressed. Tel: +30 210 727 3753; Fax: +30 210 727 3745; Email: 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.

Abbreviations: FACS, fluorescence-activated cell sorter; FBS, fetal bovine serum; FHC, familial hypercholesterolemia; LC3, microtubule-associated protein light chain 3; MDC, monodansylcadaverin; PBS, phosphate-buffered saline; Pon, ponasterone-A

Received July 7, 2006; revised November 2, 2006; accepted November 21, 2006.


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