Fatty acid synthase and adenosine monophosphate-activated protein kinase regulate cell survival and drug sensitivity in diffuse large B-cell lymphoma

Abstract

Fatty acid synthesis is crucial in supporting the survival and proliferation of multiple forms of cancer. The high metabolic demands of fatty acid synthesis are regulated by the AMP-activated kinase and activity of the fatty acid synthase enzyme. In this study, the roles of these enzymes in diffuse large B-cell lymphoma (DLBCL) were investigated by genetic knock-down and pharmacological activation of AMP-activated kinase by metformin, and selective inhibition of fatty acid synthase using the novel drug Fasnall. We observed distinct heterogeneity and adaptive plasticity of lipid metabolism in a panel of DLBCL cell lines and demonstrate the therapeutic potential of inhibiting fatty acid synthesis in a subset of DLBCL cells. The translational relevance of these in vitro data is supported by the strong correlation between AMP-activated protein kinase expression in primary DLBCL samples and disease relapse. Inhibition of fatty acid synthase with Fasnall may represent a therapeutic option for DLBCL that preferentially subverts to de novo fatty acid synthesis.

Keywords:

• Lymphoma and Non-Hodgkin disease
• pharmacotherapeutics
• cell cycle and apoptosis changes
• metabolism

Acknowledgments

The authors would like to thank Prof. Karen Dybkær (Aalborg University Hospital, Denmark) for the provision of DLBCL cell lines; the National Cancer Institute (Bethesda, Maryland, United States of America) for the use of the cell-of-origin classifier, Lymph2Cx; Professors Lee Graves and Timothy Haystead (Duke University, North Carolina, USA) for provision of the selective FASN inhibitor, Fasnall; and Assoc. Prof. Marco Herold (Walter and Eliza Hall Institute, Melbourne, Australia) for provision of plasmids for CRISPR-Cas9.

Author contributions

GG and GB designed and performed the research, analyzed the data, wrote the paper and approved the submitted and final versions. WS critically revised drafts of the paper, approved the submitted and final versions of the paper. AJG and AG contributed essential histological input and analyzed the data. QC, YS and SG performed the research.

Disclosure statement

The authors have no conflict of interests to disclose.