Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity
Why this work is in the frame
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Bibliographic record
Abstract
Hypoxia in solid tumors is associated with the development of chemoresistance. Although many studies have focused on the effect of hypoxia on drug-induced apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance has not been previously investigated. Here, we determined the effects of hypoxia on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents, including anthracyclines (daunorubicin and doxorubicin), epipodophyllotoxins (etoposide), and anthracenediones (mitoxantrone). Results revealed a high degree of heterogeneity in nuclear and cytoplasmic alterations in response to acute drug exposure; however, the majority of exposed cells displayed morphologic and biochemical changes consistent with drug-induced senescence. Hypoxia decreased only the proportion of cells in the senescent population, whereas the small proportion of cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. Similar results were obtained with human HCT116 colon carcinoma cells, indicating that the protective effect of hypoxia on drug-induced senescence is not unique to MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key regulator of cellular adaptations to hypoxia, prevented hypoxia-induced resistance. HIF-1alpha small interfering RNA also selectively abolished the hypoxia-induced changes in the senescent population, indicating that the increased survival was due to protection against drug-induced senescence. These results support a requirement for HIF-1 in the adaptations leading to drug resistance and reveal that decreased drug-induced senescence is also an important contributor to the development of hypoxia-induced resistance.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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