blockade of fatty acid synthase triggers significant apoptosis in mantle cell lymphoma封锁脂肪酸合酶触发套细胞淋巴瘤的重要细胞凋亡.pdf

Blockade of Fatty Acid Synthase Triggers Significant Apoptosis in Mantle Cell Lymphoma 1. 1. 1 2 1,2 Pascal Gelebart , Zoulika Zak , Mona Anand , Andrew Belch , Raymond Lai * 1 Department of Laboratory Medicine and Pathology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada, 2 Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada Abstract Fatty acid synthase (FASN), a key player in the de novo synthetic pathway of long-chain fatty acids, has been shown to contribute to the tumorigenesis in various types of solid tumors. We here report that FASN is highly and consistently expressed in mantle cell lymphoma (MCL), an aggressive form of B-cell lymphoid malignancy. Specifically, the expression of FASN was detectable in all four MCL cell lines and 15 tumors examined. In contrast, benign lymphoid tissues and peripheral blood mononuclear cells from normal donors were negative. Treatment of MCL cell lines with orlistat, a FASN inhibitor, resulted in significant apoptosis. Knockdown of FASN expression using siRNA, which also significantly decreased the growth of MCL cells, led to a dramatic decrease in the cyclin D1 level. b-catenin, which has been previously reported to be upregulated in a subset of MCL tumors, contributed to the high level of FASN in MCL cells, Interesting, siRNA knock-down of FASN in turn down-regulated b-catenin. In conclusion, our data supports the concept that FASN contributes to the pathogenesis of MCL, by collaborating with b-catenin. In view of its high and consistent expression in MCL, FASN inhibitors may hold promises for treating MCL. Ci