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

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

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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Crossref · 10.1074/jbc.m611763200

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Research works printed but not linked: 5

  1. Brown, 1973, Fed. Proc., 32, 2168
  2. Haeffner, 1984, Cancer Res., 44, 2668
  3. Marcelli, 1998, Cancer Res., 58, 76
  4. Swinnen, 1997, Cancer Res., 57, 1086
  5. De Schrijver, 2003, Cancer Res., 63, 3799

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Metadata

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
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
Licence
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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