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  • Title: Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line.
    Author: Panvichian R, Orth K, Pilat MJ, Day ML, Day KC, Yee C, Kamradt JM, Pienta KJ.
    Journal: Urology; 1999 Oct; 54(4):746-52. PubMed ID: 10510942.
    Abstract:
    OBJECTIVES: To attempt to identify the relationship of the key regulator molecules in paclitaxel-induced apoptosis using two metastatic cell lines: the human prostate carcinoma LNCaP line and the cervical carcinoma HeLa cell line. METHODS: Both LNCaP and HeLa cells were continuously exposed to clinically achievable concentrations of paclitaxel and observed for activation of programmed cell death as measured by cytotoxic dose-response curves, poly(adenosine diphosphate-ribose) polymerase cleavage, bcl-2 phosphorylation, and the activation of caspase-7 (interleukin-1 beta converting enzyme (ICE)-LAP3). RESULTS: Initially, we asked whether paclitaxel-induced bcl-2 phosphorylation is triggered by the spindle assembly checkpoint via an active cdc2 kinase-dependent pathway and whether phosphorylation of endogenous bcl-2 is the signal that activates cell death machinery. Paclitaxel-induced G2/M cell cycle arrest correlated with cdc2 kinase activity and bcl-2 phosphorylation. Olomoucin, a specific inhibitor of cyclin-dependent kinases, inhibited bcl-2 phosphorylation. On the basis of these studies, we then investigated whether bcl-2 was phosphorylated in a cell cycle-dependent fashion. Analysis of synchronized HeLa cells demonstrated that endogenous bcl-2 is phosphorylated in a G2/M cell cycle-dependent manner without apoptosis. CONCLUSIONS: Our results indicate that the events associated with paclitaxel-induced cytotoxicity are connected to each other and represent the signaling network of paclitaxel-induced mitotic arrest and cell death. In addition, we confirmed that the death-decision of paclitaxel-induced apoptosis is not mediated by bcl-2 phosphorylation and believe that this decision may be mediated by the activated spindle assembly checkpoint.
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