Cited by 117Cancer, Lipids, and MetabolismCholesterol and Lipid MetabolismLipid Membrane Structure and Behavior

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

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Brusselmans, Koen, Timmermans, Leen, Van de Sande, Tine, Van Veldhoven, Paul P., Guan, Guimin, Shechter, Ishaiahu, Claessens, Frank, Verhoeven, Guido, Swinnen, Johannes V.·2007·Journal of Biological Chemistry

DOI 10.1074/jbc.m611763200

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Abstract

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.

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Self-citation
Unraveling the Potential Pathogenic Role of Squalene Synthase (SQS) in Lung Cancer Using Enzyme Inhibitors as Molecular Tools
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Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer
Alioui, A., Dufour, J., Leoni, V., Loregger, A., Moeton, M., Iuliano, L., Zerbinati, C., Septier, A., Val, P., Fouache, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04653-3 · Cited by 1
Retracted

Authors: Brusselmans, K., Timmermans, L., Van de Sande, T., Van Veldhoven, P. P., Guan, G., Shechter, I., Claessens, F., Verhoeven, G., & Swinnen, J. V.
Affiliations: KU Leuven (BE)
Uniformed Services University of the Health Sciences (US)
Corresponding author: Swinnen, Johannes V.
ORCID: Claessens, Frank
Swinnen, Johannes V.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2007-06
Volume: 282
Issue: 26
Pages: 18777-18785
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m611763200
OpenAlex: W2136706193
Cited by: 116
References: 49
Citations by year: 2026: 3 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 8
FWCI: 2.69
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4872 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords: squalene synthase, cholesterol biosynthesis, lipid rafts, prostate cancer, androgens, tumor cell proliferation, cancer cell death, statins, zaragozic acid A, sterol biosynthesis
MeSH terms: Acetates, Androgens, Carbon Radioisotopes, Cell Division, Cholesterol, Detergents, Enzyme Inhibitors, Humans, Male, Promoter Regions, Genetic, Prostatic Neoplasms, RNA, Messenger, Farnesyl-Diphosphate Farnesyltransferase, Terpenes, Tricarboxylic Acids, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Cell Death, Bridged Bicyclo Compounds, Heterocyclic, Membrane Microdomains, RNA, Small Interfering, Cell Line, Tumor, Sterol Regulatory Element Binding Proteins

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

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