Oncotarget

Research Papers:

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

Yekaterina Y. Zaytseva _, Jennifer W. Harris, Mihail I. Mitov, Ji Tae Kim, D. Allan Butterfield, Eun Y. Lee, Heidi L. Weiss, Tianyan Gao and B. Mark Evers

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Oncotarget. 2015; 6:18891-18904. https://doi.org/10.18632/oncotarget.3783

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Abstract

Yekaterina Y. Zaytseva1, Jennifer W. Harris1,2, Mihail I. Mitov1, Ji Tae Kim1, D. Allan Butterfield1,3, Eun Y. Lee1,4, Heidi L. Weiss1, Tianyan Gao1, B. Mark Evers1,2

1Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA

2Department of Surgery, University of Kentucky, Lexington, Kentucky, USA

3Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA

4Pathology 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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