Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 6; pp. 1504 - 1517
• Main Authors: ZAYTSEVA, Yekaterina Y, RYCHAHOU, Piotr G, EVERS, B. Mark, GULHATI, Pat, ELLIOTT, Victoria A, MUSTAIN, William C, O'CONNOR, Kathleen, MORRIS, Andrew J, SUNKARA, Manjula, WEISS, Heidi L, LEE, Eun Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-03-2012
• Subjects: Actin; AKT protein; Animals; Antineoplastic agents; Biological and medical sciences; CD44 antigen; Cell Line, Tumor; Cell migration; Cell survival; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytoskeleton; Down-Regulation - genetics; Enzymes; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; Fatty-acid synthase; Focal adhesion kinase; Focal Adhesion Kinase 1 - analysis; Gastroenterology. Liver. Pancreas. Abdomen; Gene Knockdown Techniques; Humans; Hyaluronan Receptors - metabolism; Lipogenesis; Lipogenesis - genetics; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; Medical sciences; Membrane proteins; Metastases; Mice; Mice, Nude; Oncogene Protein v-akt - analysis; paxillin; Paxillin - analysis; Pharmacology. Drug treatments; Prognosis; Proto-Oncogene Proteins c-met - analysis; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Xenograft Model Antitumor Assays; Xenografts; Transmembrane protein; Acyltransferases; Rectal disease; Enzyme; Transferases; Colorectal cancer; Cell adhesion molecule; Malignant tumor; Metastasis; Fatty-acid synthase; Colonic disease; Signal transduction; Digestive diseases; Intestinal disease; Inhibitor; Inhibition; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-4057

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.