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J. Biol. Chem., Vol. 282, Issue 26, 18777-18785, June 29, 2007

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Squalene Synthase, a Determinant of Raft-associated Cholesterol and Modulator of Cancer Cell Proliferation^*

Koen Brusselmans¹, Leen Timmermans², Tine Van de Sande², Paul P. Van Veldhoven, Guimin Guan^¶, Ishaiahu Shechter^¶, Frank Claessens^||, Guido Verhoeven, and Johannes V. Swinnen³

From the Laboratory for Experimental Medicine and Endocrinology and Department of Molecular Cell Biology, Divisions of Pharmacology and ^||Biochemistry, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium and ^¶Department of Surgery, Uniformed Services University, School of Medicine, Bethesda, Maryland 20814-4799

Several cues for cell proliferation, migration, and survival are transmitted through lipid rafts, membrane microdomains enriched in sphingolipids and cholesterol. Cells obtain cholesterol from the circulation but can also synthesize cholesterol de novo through the mevalonate/isoprenoid pathway. This pathway, however, has several branches and also produces non-sterol isoprenoids. Squalene synthase (SQS) is the enzyme that determines the switch toward sterol biosynthesis. Here we demonstrate that in prostate cancer cells SQS expression is enhanced by androgens, channeling intermediates of the mevalonate/isoprenoid pathway toward cholesterol synthesis. Interestingly, the resulting increase in de novo synthesis of cholesterol mainly affects the cholesterol content of lipid rafts, while leaving non-raft cholesterol levels unaffected. Conversely, RNA interference-mediated SQS inhibition results in a decrease of raft-associated cholesterol. These data show that SQS activity and de novo cholesterol synthesis are determinants of membrane microdomain-associated cholesterol in cancer cells. Remarkably, SQS knock down also attenuates proliferation and induces death of prostate cancer cells. Similar effects are observed when cancer cells are treated with the chemical SQS inhibitor zaragozic acid A. Importantly, although the anti-tumor effect of statins has previously been attributed to inhibition of protein isoprenylation, the present study shows that specific inhibition of the cholesterol biosynthesis branch of the mevalonate/isoprenoid pathway also induces cancer cell death. These findings significantly underscore the importance of de novo cholesterol synthesis for cancer cell biology and suggest that SQS is a potential novel target for antineoplastic intervention.

Received for publication, December 22, 2006 , and in revised form, May 2, 2007.

^* This work was supported by a grant "Geconcerteerde Onderzoeksactie van de Vlaamse Gemeenschap," by research grants from the Fund for Scientific Research-Flanders (Belgium), and by an Interuniversity Poles of Attraction Programme-Belgian State grant, Prime Minister's Office, and the Federal Office for Scientific, Technical and Cultural Affairs. 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.

¹ A postdoctoral fellow of the Fund for Scientific Research-Flanders (Belgium).

² Research assistants of the Fund for Scientific Research-Flanders (Belgium).

³ To whom correspondence should be addressed: LEGENDO, Gasthuisberg, O&N1, Herestraat 49, bus 902, B-3000 Leuven, Belgium. Tel.: 32-16-330533; Fax: 32-16-345934; E-mail: Johan.Swinnen{at}med.kuleuven.be.

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