title: Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer.
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.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yekaterina Y
authors.initials: YY
authors.lastname: Zaytseva
authors.forename: Piotr G
authors.initials: PG
authors.lastname: Rychahou
authors.forename: Pat
authors.initials: P
authors.lastname: Gulhati
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Elliott
authors.forename: William C
authors.initials: WC
authors.lastname: Mustain
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Connor
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000032:analysis; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000032:analysis; D051419:Paxillin / Q000032:analysis; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C496061:PXN protein, human; D051419:Paxillin; D064429:Fatty Acid Synthases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051058:Oncogene Protein v-akt