Molecular basis for the accelerated senescence response to Adriamycin in MCF-7 breast and HCT-116 tumor cells
Bibliographic record
Abstract
Proc Amer Assoc Cancer Res, Volume 47, 2006 4989 Rationale. An accelerated or premature senescence response to antitumor drugs and ionizing radiation has been reported in tumor cell lines, tumor xenografts and in clinical samples. The response appears to be, in large part (but not exclusively) dependent on functional p53, induction of p21, and potentially the down regulation of cdc2 (cdk1). Previous work in our laboratory has demonstrated that induction of Adriamycin- and irradiation-induced senescence is accompanied by downregulation of c-myc protein. The current studies were designed to test the roles of p21, c-myc, cdc2, and reactive oxygen species in Adriamycin-induced senescence. We also examined whether interference with apoptosis might be permissive for senescence. Results. c -myc : A 2-hour exposure to 0.75μM Adriamycin suppressed c-myc protein in MCF-7/E6 and p53 mutant MDA-MB231 breast tumor cells. This drug-induced suppression of c-myc is likely to be a component of the accelerated senescence detected in the residual cell population that remains in a growth arrested state - whereas the bulk of the cell population dies through apoptosis. Unexpectedly, MCF-7 cells expressing exogenous c-myc (via a doxycycline-inducible promoter) also senesced in response to acute Adriamycin exposure. Furhermore, c-myc protein levels were unchanged in p53 wild-type HCT-116 cell undergoing senescence in response to Adriamycin. cdc2 : Adriamycin suppressed cdc2 expression in MCF-7/E6 cells, MDA-MB231 cells and HCT-116 cells; the effect on cdc2 was generally transient, with a partial restoration of cdc2 levels in cells that recovered proliferative capacity. p53 and p21: Adriamycin promoted accelerated senescence in HCT-116 cells; the senescence response was delayed in p53 knockout HCT-116 cells and eliminated in p21 knockout HCT-116 cells. Apoptosis was detected in both the p53 and p21 knockouts but not the wild-type cells. Reactive oxygen: The reactive oxygen scavenger, N-acetyl cysteine, blocked reactive oxygen generation in MCF-7 cells exposed to Adriamycin, but did not attenuate the accelerated senescence response. Interference with apoptosis: Blocking apoptosis in MDA-MB231 or MCF-7/E6 cells with the pan-caspase inhibitor zVAD-FMK failed to consistently increase the senescent cell population or reduce the antiproliferative activity of Adriamycin. Conclusions. Our studies suggest that suppression of c-myc and generation of reactive oxygen play limited roles in the accelerated senescence response to Adriamycin. In contrast, induction of p21 and down regulation of cdc2 may be key components of this response pathway. Senescence does not appear to be the default response when apoptosis is blocked; however, other death pathways (i.e., mitotic catastrophe or autophagy) may contribute to the antiproliferative and cytotoxic actions of Adriamycin when the senescence response pathway is abrogated.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.002 | 0.001 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".