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Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells
C Lanzi1, G Cassinelli, G Cuccuru
1Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Background:
Defects in the cell cycle machinery of prostate cancer cells might impair the efficiency of cell cycle checkpoints and affect the cell response to chemotherapeutic drugs. We examined the relationship between the status of microtubule damage-activated checkpoints and the response of hormone-refractory prostate cancer cells to paclitaxel.
Methods:
The two cell lines DU145 and PC3 harboring defects at proteins involved in the regulation of checkpoints activated by microtubule damage were examined for cell sensitivity, apoptotic response, and efficiency of checkpoints in response to paclitaxel.
Results:
In spite of a comparable sensitivity to the antiproliferative effects of paclitaxel, DU145 and PC3 cells exhibited different cell cycle control at checkpoints activated by microtubule damage. A transient mitotic arrest was induced by the taxane in both cell lines. However, PC3 cells underwent a rapid mitotic slippage and displayed a defective postmitotic checkpoint as evidenced by the appearance of polyploid cells. In this cell line, paclitaxel-induced cell death was a slow and delayed event, occurring also after S-phase re-entry. The mitotic checkpoint appeared to be more stringent in DU145 cells compared to PC3 cells. Moreover, despite the expression of mutated proteins involved in the prevention of DNA endoreduplication (p53, pRb, and p16(INK4A)), these cells did not progress into the cell cycle but efficiently underwent apoptosis by 24 hr. Such a response of DU145 cells was associated with phosphorylation of the p21(WAF1) protein.
Conclusions:
These observations evidence that activation of checkpoints following microtubule damage in prostate cancer may be regulated through complex mechanisms possibly involving p21(WAF1). Our findings support that the status of cell cycle checkpoints might affect the modality of cell death. However, the relevance of the mode of cell death for the sensitivity to taxanes remains to be determined.
Insights
Prostate cancer cells with defective cell cycle checkpoints show varied responses to paclitaxel. Checkpoint status influences cell death modality, impacting taxane sensitivity.
Area of Science:
- Oncology
- Cell Biology
- Cancer Research
Background:
- Prostate cancer cell cycle defects can affect checkpoint efficiency and drug response.
- Investigating microtubule damage-activated checkpoints in hormone-refractory prostate cancer is crucial.
Purpose of the Study:
- To examine the relationship between cell cycle checkpoint status and paclitaxel response in prostate cancer cells.
- To understand how microtubule damage checkpoints influence cell death pathways.
Main Methods:
- Utilized DU145 and PC3 prostate cancer cell lines with known checkpoint protein defects.
- Assessed cell sensitivity, apoptosis, and checkpoint efficiency in response to paclitaxel treatment.
Main Results:
- Both cell lines showed comparable sensitivity to paclitaxel's antiproliferative effects.
- PC3 cells exhibited mitotic slippage and a defective postmitotic checkpoint, leading to polyploidy and delayed apoptosis.
- DU145 cells displayed a more stringent mitotic checkpoint and underwent rapid apoptosis, associated with p21(WAF1) phosphorylation.
Conclusions:
- Prostate cancer checkpoint activation after microtubule damage involves complex mechanisms, potentially including p21(WAF1).
- Cell cycle checkpoint status significantly affects the modality of cell death in response to chemotherapy.
- The impact of cell death mode on taxane sensitivity requires further investigation.