4-methylene-2-octyl-5-oxofuran-3-carboxylic-acid and Lymphoma--Large-B-Cell--Diffuse

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.

Topics: 4-Butyrolactone; Adult; Aged; Aged, 80 and over; Apoptosis; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Fatty Acid Synthases; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Proto-Oncogene Proteins c-met; RNA, Small Interfering; Validation Studies as Topic