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Exposure to a bacterial metabolite induces specific transcriptional signature of DAF-16 regulated genes, xanthine oxidase, and Phase I detoxification enzymes in C. elegans

ABSTRACT: RNA-seq analysis of the effect of a secondary metabolite produced by Streptomyces venezuelae that enhanced oxidative stress, mitochondrial dysfunction, and neurodegeneration in Caenorhabditis elegans. Nearly all DEGs had previous evidence of an association with DAF-16 (FOXO). DEGs were also enriched for Phase I (CYP) and Phase II (UGT) detoxification genes. DEGs representing several non-CYP Phase I enzymes were identified, including down-regulation of xdh-1. XDH-1 is interconvertible with XO and S. ven metabolite exposure enhanced XO activity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE217300 | GEO | 2023/05/03

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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Exposure to a bacterial metabolite induces specific transcriptional signature of DAF-16 regulated genes, xanthine oxidase, and Phase I detoxification enzymes in C. elegans

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