Relationship between the radiosensitizing effect of wortmannin, DNA double‐strand break rejoining, and <i>p21<sup>WAF1</sup></i> induction in human normal and tumor‐derived cells
Why this work is in the frame
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Bibliographic record
Abstract
Wortmannin (WM) is a potent inhibitor of the catalytic sub-unit of DNA-PK, which is involved in one pathway of DNA double-strand break (DSB) rejoining, and of ATM, which functions upstream in the p53 signaling pathway. WM is known to be an efficient radiosensitizer in a variety of mammalian cell types, to inhibit DSB rejoining following exposure to supralethal doses (> or =30 Gy) of ionizing radiation, and to abrogate the induction of p53 at early times after radiation exposure. We report here that WM is a more effective radiosensitizer in A549 human lung carcinoma cells than in normal human fibroblasts (NHFs). In addition, WM strongly inhibits DSB rejoining in A549 cells exposed to relatively low doses (e.g., 10 Gy) of ionizing radiation, without having any detectable effect in NHFs. We further demonstrate that WM significantly potentiates the induction of p21WAF1, a p53-regulated gene that encodes for a key mediator of cell-cycle/growth arrest, when determined at late times (e.g., 24 h) after irradiation. This late WM-dependent potentiation of p21WAF1 induction following radiation exposure is observed in NHFs and in the p53 wild-type tumor cell lines A549, A172, and SKNSH, but not in the p53-deficient tumor cell lines DLD-1, HeLa, and SKNSH-E6. We conclude that: (i) inhibition of DSB rejoining by WM may be an important contributor to its radiosensitizing effect in A549 cells but not in NHFs; and (ii) radiosensitization of p53-proficient human cells by WM may in part be associated with the delayed induction of p21WAF1, which can lead to a sustained growth-arrested phenotype resembling senescence.
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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 | 0.001 | 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