Up-regulation of Hsp27 in prostate cancer cell lines induces resistance to various chemotherapeutics through Bax interaction
Bibliographic record
Abstract
2911 Introduction: Heat shock protein 27 (Hsp27) is a cytoprotective chaperone which is highly overexpressed in several human cancers such as prostate and breast. Suppression of Hsp27 expression has been shown to render human cancer cells sensitive to chemotherapeutic drug-mediated apoptosis and an antisense oligonucleotide against Hsp27 (OGX-427, OncoGenex, Vancouver, BC) is currently being evaluated in a phase I clinical trial against solid tumors. However, the mechanisms by which this multifunctional protein confers drug-resistance remain incompletely defined. Since Hsp27 inhibits intrinsic pathway activation, we hypothesize that Hsp27 could regulate drug-induced cell death by sequestering the pro-apoptotic protein Bax (Bcl-2 family) and thereby protecting cells from apoptosis. Methods: Hsp27 overexpressing or parental LNCaP cells transfected with either siRNAHsp27 or OGX-427 were treated with various stressors including MG132 (Proteosome Inhibitor), 17-AAG (Hsp90-Inhibitor) or Paclitaxel (cytotoxic agent). Cellular responses were assessed by the following methods: MTS-Assay, Flow-cytometry, Western Blot, Immunoprecipitation, Immunoflourescence and Fractionation. Results: Forced overexpression of Hsp27 increased prostate cancer cell resistance to chemotherapeutics, whereas down-regulation by siRNA or OGX-427 induced sensitivity to chemotherapeutics and enhanced apoptosis. Moreover, overexpression of Hsp27 inhibited drug-induced Bax conformational change by forming a complex with Bax. Through its interaction with Bax, Hsp27 kept Bax in the cytoplasm, thereby protecting cells from apoptosis. In contrast, Hsp27 knockdown led to Bax conformational changes resulting in the exposure of an amino-terminal epitope of Bax, translocation to the mitochondria and increased apoptosis. Conclusion: Taken together, this data suggests that elevated Hsp27 expression levels confer resistance to various classes of anticancer agents by interfering with Bax apoptotic activity. This provides further evidence that abrogation of Hsp27 can be used as a strategy to increase the efficacy of different chemotherapeutics in prostate cancer.
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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 | 0.001 |
| 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".