Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma

• Published in: Molecular cancer therapeutics 2010-05, Vol.9 (5), p.1244-1255
• Main Authors: Uddin, Shahab, Hussain, Azhar R, Ahmed, Maqbool, Bu, Rong, Ahmed, Saeeda O, Ajarim, Dahish, Al-Dayel, Fouad, Bavi, Prashant, Al-Kuraya, Khawla S
• Format: Article
• Language: English
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; Adult; Aged; Aged, 80 and over; Apoptosis - drug effects; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - mortality; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Middle Aged; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; RNA, Small Interfering - pharmacology; Validation Studies as Topic
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-09-1061

Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we investigated the role of FASN in a large series of DLBCL tissues in a tissue microarray (TMA) format followed by in vitro studies using DLBCL cell lines. FASN was found to be expressed in 62.6% DLBCL samples and was seen in highly proliferative tumors, manifested by high Ki67 (P < 0.0001). Significant association was found between tumors expressing high FASN and c-Met tyrosine kinase (P < 0.0002), as well as p-AKT (P = 0.0309). In vitro, pharmacological FASN inhibition and small interference RNA (siRNA) targeted against FASN triggered caspase-dependent apoptosis and suppressed expression of c-Met kinase in DLBCL cell lines, which further highlighted the molecular link between FASN and c-Met kinase. Finally, simultaneous targeting of FASN and c-Met with specific chemical inhibitors induced a synergistically stimulated apoptotic response in DLBCL cell lines. These findings provide evidence that FASN, via c-Met tyrosine kinase, plays a critical role in the carcinogenesis of DLBCL and strongly suggest that targeting FASN may have therapeutic value in treatment of DLBCL.