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Transcriptional profiling of human MCF7 cell lines by RNASeq

ABSTRACT: The BCL2 family of proteins regulate apoptosis by controlling mitochondrial outer membrane permeability. However, effects on mitochondrial structure and bioenergetics have also been reported. Here we comprehensively characterized the effects of BCL2 and BCL(X)L on cellular energetics in MCF7 breast cancer cells using time-lapse confocal single cell imaging and mitochondrial and cytosolic FRET reporters. We found that BCL2 and BCL(X)L increase the metabolic robustness of MCF7 cells and that this was associated with increased mitochondrial NAD(P)H and ATP levels. Experiments with the F1F0 synthase inhibitor oligomycin demonstrated that BCL2 and in particular BCL(X)L, while not affecting ATP synthase activity, more efficiently coupled the mitochondrial proton motive force with ATP production. This metabolic advantage was associated with an increased resistance to nutrient deprivation and enhanced clonogenic survival in response to metabolic stress, in the absence of profound effects on cell death. Our data suggest that a primary function of BCL(X)L and BCL2 overexpression in tumor cells is to increase their resistance to metabolic stress in the tumor microenvironment, independent of cell death signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158808 | GEO | 2020/10/01

REPOSITORIES: GEO

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Project description:Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Adccordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation, strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.

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Transcriptional profiling of human MCF7 cell lines by RNASeq

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