Abstract 4062: Clusterin downregulation sensitize prostate cancer cells to taxane by modulating mitosis.
Bibliographic record
Abstract
Abstract Clusterin (CLU) is a stress-activated molecular chaperone closely linked to treatment resistance and cancer progression. CLU is a novel therapeutic anti-cancer target with both preclinical and phase II clinical proof of concept using the antisense OGX-011 inhibitor; phase III clinical trials of combination docetaxel + OGX-011 are underway. Cytotoxic chemotherapy drugs like taxane are believed to gain selectivity by targeting cells that are in mitosis. When cultured cancer cells are treated with taxane, only cells that enter mitosis are killed or rendered senescent. Quiescent cells or cycling cells that do not reach mitosis during drug exposure are spared. In this sense, sentisizing cells to taxane can occur through mitosis regulation. In this study, we show that CLU downregulation enhances cytotoxicity of the new generation taxane cabazitaxol. Treatment of PC3 human prostate cancer cells with cabazitaxol induces G2/M arrest followed by mitotic death. Downregulation of CLU accelerated these G2/M associated events and resulted in reduced cabazitaxol EC50 and clonogenic survival upon cabazitaxol treatment. To investigate the mechanisms that allow CLU deficient cells to respond to taxane and examine whether this response is linked to a role of CLU in the control of cell cycle progression, we knocked down CLU expression in PC3 and LNCaP cells and found an accumulation of cells in G2/M phase and a reduction in cell growth. The screening of different cell cycle effectors after CLU downregulation in different cell lines and xenografts shows that CLU specifically regulates Cdc25C, while the two other Cdc25 isoforms, A and B, are not affected. Interestingly Cdc25C is a key regulator of mitosis initiation and exit. Importantly, we show that Cdc25C and CLU expression negatively correlate in prostate cancer cell lines, xenografts and human biopsies. When CLU is down regulated, Cdc25C transcription increased resulting in protein accumulation; as a consequence, cells showed G2/M blockage and slower mitotic progression. Accordingly, we suggest that down regulation of CLU alters sensitivity to taxane by modulating exit from mitosis, which is controlled by Cdc25C. Citation Format: Nader Al Nakouzi, Eliana Beraldi, Stuart Shepherd, Yohann Loriot, Soojin Kim, Lauren Leichmann, Amina Zoubeidi, Martin E Gleave. Clusterin downregulation sensitize prostate cancer cells to taxane by modulating mitosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4062. doi:10.1158/1538-7445.AM2013-4062
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How this classification was reachedexpand
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 | 0.001 |
| 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) | 0.003 | 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 teacher head, 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".