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Cited by 153Cancer, Lipids, and MetabolismLipid metabolism and biosynthesisCancer, Hypoxia, and Metabolism

Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration

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Zaytseva, Yekaterina Y., Harris, Jennifer W., Mitov, Mihail I., Kim, Ji Tae, Butterfield, D. Allan, Lee, Eun Y., Weiss, Heidi L., Gao, Tianyan +1 more·2015·Oncotarget
DOI 10.18632/oncotarget.3783PMC PMC4662462
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Abstract

// Yekaterina Y. Zaytseva 1 , Jennifer W. Harris 1, 2 , Mihail I. Mitov 1 , Ji Tae Kim 1 , D. Allan Butterfield 1, 3 , Eun Y. Lee 1, 4 , Heidi L. Weiss 1 , Tianyan Gao 1 , B. Mark Evers 1, 2 1 Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA 2 Department of Surgery, University of Kentucky, Lexington, Kentucky, USA 3 Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA 4 Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky, USA Correspondence to: B. Mark Evers, e-mail: mark.evers@uky.edu Keywords: FASN, colorectal cancer, energy homeostasis, metastasis, metabolic stress Received: March 11, 2015 Accepted: April 6, 2015 Published: April 20, 2015 ABSTRACT Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells and orthotopic CRCs. Immunohistochemical evaluation demonstrated increased expression of FASN and p62, a marker of autophagy inhibition, in primary CRCs and liver metastases compared to matched normal colonic mucosa. Our findings indicate that overexpression of FASN plays a crucial role in maintaining energy homeostasis in CRC via increased oxidation of endogenously synthesized lipids. Importantly, activation of fatty acid oxidation and consequent downregulation of stress-response signaling pathways may be key adaptation mechanisms that mediate the effects of FASN on cancer cell survival and metastasis, providing a strong rationale for targeting this pathway in advanced CRC.

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Cited by

Sorted by citations

Authors
Zaytseva, Y. Y., Harris, J. W., Mitov, M. I., Kim, J. T., Butterfield, D. A., Lee, E. Y., Weiss, H. L., Gao, T., & Evers, B. M.
Affiliations
University of Kentucky (US)
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2015-04-20
Volume
6
Issue
22
Pages
18891-18904
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.3783
PMC
PMC4662462
OpenAlex
W1485543117
Cited by
153
References
7
Citations by year
2026: 9 · 2025: 21 · 2024: 17 · 2023: 10 · 2022: 11 · 2021: 22 · 2020: 17 · 2019: 14 · 2018: 13 · 2017: 12 · 2016: 5 · 2015: 2
FWCI
3.53
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Cancer Institute (CA165990, P30CA177558, T32CA160003, T32CA165990)
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 › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
fatty acid synthase, colorectal cancer, cellular respiration, fatty acid oxidation, energy homeostasis, lipid droplets, autophagy inhibition, p62, metabolic stress, liver metastasis, tumor cell survival, de novo lipogenesis, metabolic adaptation
MeSH terms
Cell Survival, Glycolysis, Humans, Colorectal Neoplasms, Signal Transduction, Transcriptional Activation, Up-Regulation, Cell Respiration, HT29 Cells, HCT116 Cells, Cell Line, Tumor, Fatty Acid Synthase, Type I

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