PMID- 30538285 OWN - NLM STAT- MEDLINE DCOM- 20200831 LR - 20211204 IS - 1476-5403 (Electronic) IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 26 IP - 9 DP - 2019 Sep TI - By reducing global mRNA translation in several ways, 2-deoxyglucose lowers MCL-1 protein and sensitizes hemopoietic tumor cells to BH3 mimetic ABT737. PG - 1766-1781 LID - 10.1038/s41418-018-0244-y [doi] AB - 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 and protein glycosylation in the endoplasmic reticulum (ER). Its glycolysis inhibition lowered ATP and, through the AMPK/mTORC1 pathway, markedly reduced global protein synthesis, as did an ER integrated stress response. A dual reporter assay revealed that 2DG impeded not only cap-dependent translation but also elongation or cap-independent translation. MCL-1 protein fell markedly, whereas 12 other BCL-2 family members were unaffected. We ascribe the MCL-1 drop to the global fall in translation, exacerbated for mRNAs with a structured 5' untranslated region (5'UTR) containing potential regulatory motifs like those in MCL-1 mRNA and the short half-life of MCL-1 protein. Pertinently, 2DG downregulated two other short-lived oncoproteins, MYC and MDM2. Thus, our results support MCL-1 as a critical 2DG target, but also reveal multiple effects on global translation that may well also affect its promotion of apoptosis. FAU - Tailler, Maximilien AU - Tailler M AD - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. AD - Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia. FAU - Lindqvist, Lisa M AU - Lindqvist LM AUID- ORCID: 0000-0002-2421-2740 AD - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. AD - Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia. AD - CSL Ltd, Parkville, VIC, Australia. FAU - Gibson, Leonie AU - Gibson L AD - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. FAU - Adams, Jerry M AU - Adams JM AD - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. adams@wehi.edu.au. AD - Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia. adams@wehi.edu.au. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181211 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (BCL2 protein, human) RN - 0 (Bax protein (53-86)) RN - 0 (Biphenyl Compounds) RN - 0 (MCL1 protein, human) RN - 0 (Myeloid Cell Leukemia Sequence 1 Protein) RN - 0 (Peptide Fragments) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (RNA, Messenger) RN - 9G2MP84A8W (Deoxyglucose) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Apoptosis/drug effects MH - Apoptosis Regulatory Proteins MH - Biomimetics MH - Biphenyl Compounds MH - Cell Line, Tumor MH - Deoxyglucose/pharmacology MH - Endoplasmic Reticulum/drug effects/genetics MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Myeloid Cell Leukemia Sequence 1 Protein/*genetics MH - Peptide Fragments/*genetics MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/pathology MH - *Protein Biosynthesis MH - Protein Kinases/genetics MH - Proto-Oncogene Proteins/*genetics MH - Proto-Oncogene Proteins c-bcl-2/genetics MH - RNA, Messenger/genetics PMC - PMC6748140 COIS- The authors affirm that, as The Walter and Eliza Hall Institute contributed with Genentech and Abbott (now AbbVie) to the development of ABT199, it now receives royalty and milestone payments, some of which will go to them. EDAT- 2018/12/13 06:00 MHDA- 2020/09/01 06:00 PMCR- 2018/12/11 CRDT- 2018/12/13 06:00 PHST- 2018/07/13 00:00 [received] PHST- 2018/11/15 00:00 [accepted] PHST- 2018/10/30 00:00 [revised] PHST- 2018/12/13 06:00 [pubmed] PHST- 2020/09/01 06:00 [medline] PHST- 2018/12/13 06:00 [entrez] PHST- 2018/12/11 00:00 [pmc-release] AID - 10.1038/s41418-018-0244-y [pii] AID - 244 [pii] AID - 10.1038/s41418-018-0244-y [doi] PST - ppublish SO - Cell Death Differ. 2019 Sep;26(9):1766-1781. doi: 10.1038/s41418-018-0244-y. Epub 2018 Dec 11.