Increased Expression of Fatty Acid Synthase Provides a Survival Advantage to Colorectal Cancer Cells via Upregulation of Cellular Respiration

Authors

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

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.

Document Type

Article

Publication Date

8-7-2015

Notes/Citation Information

Published in Oncotarget, v. 6, no. 22, p. 18891-18904.

Copyright @ 2016 Impact Journals, LLC

Licensed under a Creative Commons Attribution 3.0 License.

Digital Object Identifier (DOI)

http://dx.doi.org/10.18632/oncotarget.3783

Funding Information

This research was supported by NIH grant T32 CA165990 and NCI grant P30 CA177558 (for shared resource facilities).

Repository Citation

Zaytseva, Yekaterina Y.; Harris, Jennifer W.; Mitov, Mihail I.; Kim, Ji Tae; Butterfield, D. Allan; Lee, Eun Young; Weiss, Heidi L.; Gao, Tianyan; and Evers, B. Mark, "Increased Expression of Fatty Acid Synthase Provides a Survival Advantage to Colorectal Cancer Cells via Upregulation of Cellular Respiration" (2015). Markey Cancer Center Faculty Publications. 58.
https://uknowledge.uky.edu/markey_facpub/58