title: Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration.
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.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Yekaterina Y
authors.initials: YY
authors.lastname: Zaytseva
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.|Department of Surgery, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Harris
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Mihail I
authors.initials: MI
authors.lastname: Mitov
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Ji Tae
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.|Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.|Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Gao
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.|Department of Surgery, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D006019:Glycolysis; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I
keywords: FASN; colorectal cancer; energy homeostasis; metabolic stress; metastasis