Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells

BACKGROUND. Defects in the cell cycle machinery of prostate cancer cells mi ght impair the efficiency of cell cycle checkpoints and affect the cell res ponse to chemotherapeutic drugs. We examined the relationship between the s tatus of microtubule damage-activated checkpoints and the response of hormo ne-refractory prostate cancer cells to paclitaxel. METHODS. The two cell lines DU145 and PC3 harboring defects at proteins inv olved in the regulation of checkpoints activated by microtubule damage were examined for cell sensitivity, apoptotic response, and efficiency of check points in response to paclitaxel. RESULTS. In spite of a comparable sensitivity to the antiproliferative effe cts of paclitaxel, DU145 and PC3 cells exhibited different cell cycle contr ol at checkpoints activated by microtubule damage. A transient mitotic arre st was induced by the taxane in both cell lines. However, PC3 cells underwe nt a rapid mitotic slippage and displayed a defective postmitotic checkpoin t as evidenced by the appearance of polyploid cells. In this cell line, pac litaxel-induced cell death was a slow and delayed event, occurring also aft er S-phase re-entry. The mitotic checkpoint appeared to be more stringent i n DU145 cells compared to PC3 cells. Moreover, despite the expression of mu tated proteins involved in the prevention of DNA endoreduplication (p53, pR b, and p16(INK4A)), these cells did not progress into the cell cycle but ef ficiently 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 fol lowing microtubule damage in prostate cancer may be regulated through compl ex mechanisms possibly involving p21(WAF1). Our findings support that the s tatus of cell cycle checkpoints might affect the modality of cell death. Ho wever, the relevance of the mode of cell death for the sensitivity to taxan es remains to be determined. (C) 2001 Wiley-Liss, Inc.