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J. Biol. Chem., Vol. 283, Issue 4, 2231-2245, January 25, 2008

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Quercetin 3-Glucoside Protects Neuroblastoma (SH-SY5Y) Cells in Vitro against Oxidative Damage by Inducing Sterol Regulatory Element-binding Protein-2-mediated Cholesterol Biosynthesis^*

Ramani Soundararajan¹, Alexander D. Wishart², H. P. Vasantha Rupasinghe, Mayi Arcellana-Panlilio^¶, Carolanne M. Nelson^||, Michael Mayne^**, and George S. Robertson³

From the Department of Pharmacology and Departments of Psychiatry and Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada, the Department of Environmental Sciences, Nova Scotia Agricultural College, Truro, Nova Scotia B2N 5E3, Canada, the ^¶Department of Biochemistry and Molecular Biology, University of Calgary, HM 393b-3330 Hospital Drive, N.W., Calgary, Alberta T2N 4N1, Canada, the ^||Department of Family and Nutritional Sciences, University of Prince Edward Island, Charlottetown, Prince Edward Island C1A 4P3, Canada and the ^**Institute for Nutrisciences and Health, National Research Council of Canada, Charlottetown, Prince Edward Island C1A 5T1, Canada

The flavonoid quercetin 3-glucoside (Q3G) protected SH-SY5Y, HEK293, and MCF-7 cells against hydrogen peroxide-induced oxidative stress. cDNA microarray studies suggested that Q3G-pretreated cells subjected to oxidative stress up-regulate the expression of genes associated with lipid and cholesterol biosynthesis. Q3G pretreatment elevated both the expression and activation of sterol regulatory element-binding protein-2 (SREBP-2) only in SH-SY5Y cells subjected to oxidative stress. Inhibition of SREBP-2 expression by small interfering RNA or small molecule inhibitors of 2,3-oxidosqualene:lanosterol cyclase or HMG-CoA reductase blocked Q3G-mediated cytoprotection in SH-SY5Y cells. By contrast, Q3G did not protect either HEK293 or MCF-7 cells via this signaling pathway. Moreover, the addition of isopentenyl pyrophosphate rescued SH-SY5Y cells from the inhibitory effect of HMG-CoA reductase inhibition. Last, Q3G pretreatment enhanced the incorporation of [¹⁴C]acetate into [¹⁴C]cholesterol in SH-SY5Y cells under oxidative stress. Taken together, these studies suggest a novel mechanism for flavonoid-induced cytoprotection in SH-SY5Y cells involving SREBP-2-mediated sterol synthesis that decreases lipid peroxidation by maintaining membrane integrity in the presence of oxidative stress.

Received for publication, April 30, 2007 , and in revised form, November 20, 2007.

The microarray data has been deposited to the NCBI gene expression and hybridization array repository (GEO; http://www.ncbi.nlm.nih.gov/geo), and GEO accession numbers are GSE6199 [NCBI GEO] , GSE6200 [NCBI GEO] , GSM143163 [NCBI GEO] , GSM143243 [NCBI GEO] , GSM143247 [NCBI GEO] , GSM143248 [NCBI GEO] , GSM143249 [NCBI GEO] , GSM143250 [NCBI GEO] , GSM143251 [NCBI GEO] , GSM143252 [NCBI GEO] , GSM143253 [NCBI GEO] , GSM143254 [NCBI GEO] , GSM143255 [NCBI GEO] , GSM143256 [NCBI GEO] , GSM143257 [NCBI GEO] , GSM143258 [NCBI GEO] , GSM143259 [NCBI GEO] , and GSM143260 [NCBI GEO] .

^* This work was supported in part by grants from Atlantic Canada Opportunities Agency-Atlantic Innovation Funds (to C. M. N. and G. S. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

¹ Supported by a Postdoctoral fellowship from the Department of Family and Nutritional Sciences, University of Prince Edward Island.

² Supported by a studentship from Vaccinium Technologies Inc.

³ To whom correspondence should be addressed: Dept. of Psychiatry and Pharmacology, Sir Charles Tupper Medical Bldg., Dalhousie University, 5850 College St., Halifax, Nova Scotia B3H 1X5, Canada. Tel.: 902-494-1528; Fax: 902-494-1388; E-mail: George.Robertson{at}dal.ca.

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