Abstract
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.
Highlights
Perturbed regulation of apoptosis can promote cancer and affect its treatment [1, 2]
We first determined the efficacy of 2DG plus ABT737 on eight well-characterized human hemopoietic tumor cell lines (Fig. 1a)
Significance was determined by one-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; ns, not significant. b FACS analysis of cell death protection by caspase inhibitor Q-VD (50 μM) during 24 h treatment with 2DG (1 mM) and BH3 mimetic ABT737 or ABT199 (0.5 μM)
Summary
Perturbed regulation of apoptosis can promote cancer and affect its treatment [1, 2]. The interactions of three BCL-2 protein sub-families govern its regulation. An exciting new approach to cancer therapy, promising for hematopoietic malignancies, is targeting one or more pro-survival BCL-2 family member with small molecules that engage pro-survival proteins to their natural BH3-only antagonists [1, 3]. The first potent authentic ‘‘BH3 mimetic’’, ABT737 [4], inhibits BCL-2, BCL-XL, and BCL-W but not MCL-1 [4, 5]. Underscoring the potential of BH3 mimetics, in 2016 the FDA approved the BCL-2-specific ABT199 (venetoclax) for treating refractory chronic lymphocytic leukemia. In tumor cells treated with ABT737, MCL-1 is a prime resistance factor [5,6,7,8], emphasizing the need for agents providing complementary function
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