orlistat and Lymphoma--Mantle-Cell

Imbalances in the composition of BCL2 family proteins contribute to tumourigenesis and therapy resistance of mantle cell lymphoma (MCL), making these proteins attractive therapy targets. We studied the efficiency of dual targeting the NOXA/MCL1 axis by combining fatty acid synthase inhibitors (NOXA stabilization) with the CDK inhibitor Dinaciclib (MCL1 reduction). This combination synergistically induced apoptosis in cell lines and primary MCL cells and led to almost complete inhibition of tumour progression in a mouse model. Apoptosis was NOXA-dependent and correlated with the NOXA/MCL1 ratio, highlighting the importance of the NOXA/MCL1 balance for effective cell death induction in MCL.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclic N-Oxides; Cyclin-Dependent Kinases; Enzyme Inhibitors; Female; Humans; Indolizines; Lactones; Lymphoma, Mantle-Cell; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Orlistat; Proto-Oncogene Proteins c-bcl-2; Pyridinium Compounds

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. β-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 β-catenin. In conclusion, our data supports the concept that FASN contributes to the pathogenesis of MCL, by collaborating with β-catenin. In view of its high and consistent expression in MCL, FASN inhibitors may hold promises for treating MCL.

Topics: Antineoplastic Agents; Apoptosis; beta Catenin; Caspases; Cell Line, Tumor; Cell Survival; Cyclin D; Endopeptidases; Fatty Acid Synthases; Gene Knockdown Techniques; Humans; Lactones; Lymphoma, Mantle-Cell; Orlistat; Promoter Regions, Genetic; RNA Interference; Transcription, Genetic; Ubiquitin Thiolesterase