Mitochondrial DNA depletion promotes impaired oxidative status and adaptive resistance to apoptosis in T47D breast cancer cells
Why this work is in the frame
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Bibliographic record
Abstract
The mutation and reduction of mitochondrial DNA (mtDNA) have been extensively detected in human cancers. The effects of mitochondrial dysfunction are particularly important in breast cancer, because estrogen-mediated metabolites generate large quantities of local reactive oxygen species in the breast, which directly bind to mtDNA and facilitate neoplastic transformation. To further elucidate the molecular roles of mtDNA in breast cancer, we determined the oxidative status of a breast tumor cell line lacking mtDNA (T47D ρ⁰) and analyzed its susceptibility after exposure to various anticancer drugs as well as different proapoptotic signals. Our data showed that T47D ρ⁰ cells generated significantly increased levels of lactate with concomitantly reduced oxygen consumption and ATP production compared with the wild-type (WT). The amount of reactive oxygen species generation in ρ cells was lowered to approximately 12% that of parental cells, as evidenced by the oxidation of redox-sensitive probes. Although mtDNA depletion did not affect the expression of superoxide dismutase or its activity, the activities of antioxidant enzymes, catalase and glutathione peroxidase, were significantly higher in ρ⁰ cells compared with WT cells. In addition, mtDNA-depleted cells displayed a decreased sensitivity and accumulation of chemotherapeutic drugs (doxorubicin, vincristine, and paclitaxel), potentially because of the upregulated expression of multidrug resistance 1 (MDR1) gene and its product P-glycoprotein. When compared with their WT counterparts, T47D ρ⁰ cells were also more resistant to apoptosis induced by varying concentrations of staurosporine and anti-Fas antibody. Altogether, our results indicate the importance of intact mtDNA for maintaining the proper intracellular oxidative status. These data provide evidence for a possible role of mtDNA content reduction in acquiring an apoptosis-resistant phenotype during breast tumor progression and might contribute to effective therapeutic strategies for this common malignancy.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it