Inhibition of Fatty Acid Synthase Suppresses c-Met Receptor Kinase and Induces Apoptosis in Diffuse Large B-Cell Lymphoma

Abstract

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. Mol Cancer Ther; 9(5); 1244-55. ©2010 AACR.

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

“…FASN inhibition has also been described as a sensitizer for cisplatin treatment in mice xenografted with human ovarian cancer cells (30). In fact, FASN is highly expressed across a wide range of human tumor types where its inhibition either induces apoptosis and/or synergizes with cytotoxic agents (31)(32)(33)(34)(35)(36)(37)(38). Consistent with these data, we show that inhibition of FASN with short hairpin RNAs also sensitized our CDH1-deficient cells to cisplatin treatment.…”

FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Expression

“…Previous studies by many groups have shown that FASN overexpression or inhibition modulates Akt as well as other drivers of oncogenic signaling that include c-Met, ERBB2, EGFR, and Wnt-b-catenin (Ventura et al, 2015, Coleman et al, 2009, Uddin et al, 2010, Hu et al, 2016, Puig et al, 2011, Vazquez-Martin et al, 2008, Bollu et al, 2015). Our observation that combining TVB-3166 or TVB-3664 with taxane treatment increased efficacy in several tumor models of diverse origin and genetic features suggests the primary mechanism is fundamental to tumor cell biology and the taxane mechanism of action such as tubulin palmitoylation, expression, and the disruption of microtubule function; however, complementary mechanism may play an important role in a manner that is dependent upon tumor type.…”

The role of HGF/c-MET signaling pathway in lymphoma

“…It is recently reported that fatty acid synthase (FAS) inhibition triggered caspase-dependent apoptosis and suppressed the expression of c-MET in DLBCL cell lines [32]. Pharmacological FAS blockade might result in rapid changes in the lipid composition of the tumor cell membrane, which could impair a correct cellular localization of c-MET [33]. Moreover, FAS inhibition may cause an imbalance in the membrane phospholipids levels, which may result in decreased c-MET membrane localization and activation [34].…”