By reducing global mRNA translation in several ways, 2-deoxyglucose lowers MCL-1 protein and sensitizes hemopoietic tumor cells to BH3 mimetic ABT737
Maximilien Tailler, Lisa M Lindqvist, Leonie Gibson, Jerry M Adams
Cell Death & Differentiation | NATURE PUBLISHING GROUP | Published : 2019
Drugs targeting various pro-survival BCL-2 family members (''BH3 mimetics'') have efficacy in hemopoietic malignancies, but the non-targeted pro-survival family members can promote resistance. Pertinently, the sensitivity of some tumor cell lines to BH3 mimetic ABT737, which targets BCL-2, BCL-XL, and BCL-W but not MCL-1, is enhanced by 2-deoxyglucose (2DG). We found that 2DG augmented apoptosis induced by ABT737 in 3 of 8 human hemopoietic tumor cell lines, most strongly in pre-B acute lymphocytic leukemia cell line NALM-6, the focus of our mechanistic studies. Although 2DG can lower MCL-1 translation, how it does so is incompletely understood, in part because 2DG inhibits both glycolysis a..View full abstract
Awarded by National Health and Medical Research Council
Awarded by SCOR grant from the Leukemia and Lymphoma Society
Awarded by Australian Government Independent Research Institute Infrastructure Support Scheme
We thank Dr. Philippe Bouillet for help and advice on cloning and Dr. Christophe Lefevre for help in the RT-qPCR statistical analysis. The pCDNA3/Ren/HCV/FF plasmid was kindly provided by Prof Jerry Pelletier and Dr. Francis Robert (McGill University, Canada). Silvestrol was made at the Bio21 institute (Parkville) by Jennifer M. Chambers and Mark A. Rizzacasa. BOK antibody was kindly provided by Prof. Thomas Kaufmann (Bern University, Switzerland). ABT737 and ABT199 were kindly provided by Dr. David Segal and Prof. David Huang (WEHI). This work was supported by program grant 1113133 from the National Health and Medical Research Council (to JA) and SCOR grant 7015-18 from the Leukemia and Lymphoma Society (to JA), as well as operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support Program.