Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in the human LNCaP prostate tumour model
Bibliographic record
Abstract
The paper by Zellweger et al. builds on the continuing story of clusterin (TRPM‐2) in the development and progression of prostate cancer. This group have published a series of papers on this protein, showing that it correlates with progression to androgen‐independence and resistance to apoptosis. One of their recent papers has shown that ‘knocking out’ clusterin increases radiation sensitivity in prostate cancer cells. The current paper reports that increasing the expression of clusterin in LNCaP cells increases the cell's resistance to radiation‐induced apoptosis. Manipulating identified survival proteins has important implications in preventing androgen‐independent progression. Clusterin is such a survival protein and represents an important drug target in the near future. OBJECTIVE To evaluate the effect of clusterin overexpression on radiation‐induced tumour growth rates and apoptosis in human prostate LNCaP cells, as prostate cancer cells are relatively resistant to radiation‐induced apoptosis and local recurrences are common, but overexpression of the anti‐apoptotic protein clusterin can accelerate progression to androgen‐independence and to confer a chemoresistant phenotype in various prostate cancer models. MATERIALS AND METHODS Western blot analysis and immunohistochemistry were used to compare clusterin expression levels in parental (P) and clusterin‐transfected (T) LNCaP cells in vitro and in vivo . The effects of radiation on clusterin‐expression in both parental LNCaP/P and clusterin‐transfected LNCaP/T tumours were analysed by Northern blot analysis. The cellular response to radiation was determined up to 3 weeks after irradiation using tetrazolium and re‐growth assays, and cell‐cycle analysis by flow cytometry. RESULTS Clusterin mRNA expression increased from undetectable to low levels in LNCaP/P tumours after radiation and more than three‐fold in LNCaP/T tumours. Clusterin overexpression decreased the radiosensitivity in a time‐dependent manner, reducing the extent of growth arrest and apoptosis by up to 54%. Re‐growth assays showed that the improved survival rates of LNCaP/T cells after radiation did not change after 3 days, remaining constant over 3 weeks. CONCLUSIONS These results identify clusterin as a promoter of cell survival that may help mediate resistance to radiation‐induced apoptosis. Furthermore, clusterin overexpression seems to provide an extended protection against radiation‐induced cell cycle arrest and apoptosis.
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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 | 0.001 | 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 | 0.000 |
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 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".