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Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer
Open accessPublished version of a preprint
Abstract
Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of CD44, a transmembrane protein associated with metastases in several cancers including CRC. In addition, inhibition of lipogenic enzymes and reduced expression of CD44 attenuated the activation of MET, Akt, FAK, and paxillin, which are known to regulate adhesion, migration, and invasion. These changes were consistent with an observed decrease in migration and adhesion of CRC cells in functional assays and with reorganization of actin cytoskeleton upon FASN inhibition. Despite the modest effect of FASN inhibition on tumor growth in xenografts, attenuation of lipogenesis completely abolished establishment of hepatic metastasis and formation of secondary metastasis. Together, our findings suggest that targeting de novo lipogenesis may be a potential treatment strategy for advanced CRC.
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“We have previously reported that overexpression of FASN promotes CRC growth and metastasis via multiple mechanisms including upregulation of Cyclin D1 and VEGF secretion [10,29,47,49].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [29]
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“We and others have previously reported that FASN is highly expressed in CRC [29,30].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [29]
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Metadata
- Authors
- Zaytseva, Y. Y., Rychahou, P. G., Gulhati, P., Elliott, V. A., Mustain, W. C., O'Connor, K., Morris, A. J., Sunkara, M., Weiss, H. L., Lee, E. Y., & Evers, B. M.
- Affiliations
- University of Kentucky (US)
- Authors' Affiliations: 1Markey Cancer Center, Departments of 2Surgery and 3Pathology and Laboratory Medicine, 4Division of Cardiovascular Medicine, and 5Gill Heart Institute, University of Kentucky, Lexington, Kentucky
- Corresponding author
- Evers, B. Mark
- ORCID
- Venue
- Cancer Research
- Published
- 2012-03-14
- Volume
- 72
- Issue
- 6
- Pages
- 1504-1517
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3596828
- OpenAlex
- W1997243908
- Cited by
- 208
- References
- 52
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 19 · 2023: 12 · 2022: 17 · 2021: 19 · 2020: 17 · 2019: 11 · 2018: 18 · 2017: 8 · 2016: 19 · 2015: 13 · 2014: 22 · 2013: 7 · 2012: 3
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- Funders
- National Cancer Institute (P20CA150343, R01CA109136, P20CA1530343, T32CA165990)
- National Institute of General Medical Sciences (GM-50388, R01GM050388)
- National Center for Research Resources (S10RR026884, S10RR024598, P20RR021954)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- fatty acid synthase, ATP citrate lyase, de novo lipogenesis, colorectal cancer, liver metastasis, CD44, C-MET signaling, Akt signaling, focal adhesion kinase, paxillin, cell migration, cell adhesion, actin cytoskeleton
- MeSH terms
- Animals, Humans, Liver Neoplasms, Male, Mice, Nude, Colorectal Neoplasms, Signal Transduction, Down-Regulation, Hyaluronan Receptors, Proto-Oncogene Proteins c-met, Xenograft Model Antitumor Assays, Cell Line, Tumor, Lipogenesis, Oncogene Protein v-akt, Mice, Focal Adhesion Kinase 1, Paxillin, Gene Knockdown Techniques, Fatty Acid Synthases
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