ArticleOncogenesis2013
Mitochondrial DNA depletion sensitizes cancer cells to PARP inhibitors by translational and post-translational repression of BRCA2.
Article in Oncogenesis, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- The Role of Mitochondrial DNA Variation in Drug Response: A Systematic Review.Frontiers in genetics · 2021Pooled it
- Decoding DNA metabolism and its clinical relevance through the lens of high-throughput sequencing assays.Medical review (2021) · 2026Review
- Dual Inhibition of PARP and Akt Induces Metabolic Collapse and Apoptosis in Breast Cancer Cells.Cancers · 2025Article
- Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.International journal of molecular sciences · 2025Review
- Mitochondrial involvement in PC: improving therapeutic strategies.Frontiers in pharmacology · 2025Review
- Defects in the Mitochondrial Genome of Dogs with Recurrent Tumours.International journal of molecular sciences · 2024Article
- Review
- Mitochondrial metabolism: a predictive biomarker of radiotherapy efficacy and toxicity.Journal of cancer research and clinical oncology · 2023Review
- Mitochondria in Cancer Stem Cells: From an Innocent Bystander to a Central Player in Therapy Resistance.Stem cells and cloning : advances and applications · 2023Review
- HrpA anchors meningococci to the dynein motor and affects the balance between apoptosis and pyroptosis.Journal of biomedical science · 2022Article
- Identification of DNA Repair-Related Genes Predicting Clinical Outcome for Thyroid Cancer.Journal of oncology · 2022Article
- Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases.Diseases (Basel, Switzerland) · 2021Review
- Post-Translational Modifications That Drive Prostate Cancer Progression.Biomolecules · 2021Review
- Review
- Mitochondria at the Crossroads of Physiology and Pathology.Journal of clinical medicine · 2020Article
- Metabolic Plasticity in Chemotherapy Resistance.Frontiers in oncology · 2020Review
- miR-1245a promotes the proliferation and invasion of colon adenocarcinoma by targeting BRCA2.Annals of translational medicine · 2019Article
- Mitochondrial Dysfunction in Aging and Cancer.Journal of clinical medicine · 2019Review
- 6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner.Cancers · 2019Article
- Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells.Cancers · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Previous studies have shown that pharmacologic inhibition of poly (ADP-ribose) polymerase (PARP), a nuclear protein that is crucial in signaling single-strand DNA breaks, is synthetically lethal to cancer cells from patients with genetic deficiency in the DNA repair proteins BRCA1 and BRCA2. Herein, we demonstrate that depletion of the mitochondrial genome (mtDNA) in breast, prostate and thyroid transformed cells resulted in elevated steady-state cytosolic calcium concentration and activation of calcineurin/PI3-kinase/AKT signaling leading to upregulation of miR-1245 and the ubiquitin ligase Skp2, two potent negative regulators of the tumor suppressor protein BRCA2, thus resulting in BRCA2 protein depletion, severe reduction in homologous recombination (HR) and increased sensitivity to the PARP inhibitor rucaparib. Treatment of mtDNA-depleted cells with the PI3-kinase inhibitor LY294002, the calmodulin antagonist W-7, the calcineurin inhibitor FK506, the calcium chelator BAPTA-AM, or suppression of AKT activity by AKT small-interfering RNA (siRNA) enhanced BRCA2 protein levels as well as HR. Decreasing the intracellular calcium levels using BAPTA, or direct reconstitution of BRCA2 protein levels either by recombinant expression or by small molecule inhibition of both Skp2 and miR-1245 restored sensitivity to rucaparib to wild-type levels. Furthermore, by studying prostate tissue specimens from prostate carcinoma patients we found a direct correlation between the presence of mtDNA large deletions and loss of BRCA2 protein in vivo, suggesting that mtDNA status may serve as a marker to predict therapeutic efficacy to PARP inhibitors. In summary, our results uncover a novel mechanism by which mtDNA depletion restrains HR, and highlight the role of mtDNA in regulating sensitivity to PARP inhibitors in transformed cells.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.