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    Please use this identifier to cite or link to this item: http://asiair.asia.edu.tw/ir/handle/310904400/4614

    Title: Role of glycogen synthase kinase 3beta rapamycin-mediated cell cycle regulation and chemosensitivity
    Authors: Dong, J.;Peng, J.;Zhang, H.;Mondesire, W. H.;Jian, W.;Mills, G. B.;Mien-Chie Hung;Funda Meric-Bernstam
    Keywords: rapamycin;mTOR;cyclin D1;GSK3?;protein stability;paclitaxel
    Date: 2005-03
    Issue Date: 2009-11-27 13:57:04 (UTC+8)
    Publisher: Asia University
    Abstract: The mammalian target of rapamycin is a serine-threonine kinase that regulates cell cycle progression. Rapamycin and its analogues inhibit the mammalian target of rapamycin and are being actively investigated in clinical trials as novel targeted anticancer agents. Although cyclin D1 is down-regulated by rapamycin, the role of this down-regulation in rapamycin-mediated growth inhibition and the mechanism of cyclin D1 down-regulation are not well understood. Here, we show that overexpression of cyclin D1 partially overcomes rapamycin-induced cell cycle arrest and inhibition of anchorage-dependent growth in breast cancer cells. Rapamycin not only decreases endogenous cyclin D1 levels but also decreases the expression of transfected cyclin D1, suggesting that this is at least in part caused by accelerated proteolysis. Indeed, rapamycin decreases the half-life of cyclin D1 protein, and the rapamycin-induced decrease in cyclin D1 levels is partially abrogated by proteasome inhibitor N-acetyl-leucyl-leucyl-norleucinal. Rapamycin treatment leads to an increase in the kinase activity of glycogen synthase kinase 3? (GSK3?), a known regulator of cyclin D1 proteolysis. Rapamycin-induced down-regulation of cyclin D1 is inhibited by the GSK3? inhibitors lithium chloride, SB216763, and SB415286. Rapamycin-induced G1 arrest is abrogated by nonspecific GSK3? inhibitor lithium chloride but not by selective inhibitor SB216763, suggesting that GSK3? is not essential for rapamycin-mediated G1 arrest. However, rapamycin inhibits cell growth significantly more in GSK3? wild-type cells than in GSK3?-null cells, suggesting that GSK3? enhances rapamycin-mediated growth inhibition. In addition, rapamycin enhances paclitaxel-induced apoptosis through the mitochondrial death pathway; this is inhibited by selective GSK3? inhibitors SB216763 and SB415286. Furthermore, rapamycin significantly enhances paclitaxel-induced cytotoxicity in GSK3? wild-type but not in GSK3?-null cells, suggesting a critical role for GSK3? in rapamycin-mediated paclitaxel-sensitization. Taken together, these results show that GSK3? plays an important role in rapamycin-mediated cell cycle regulation and chemosensitivity and thus significantly potentiates the antitumor effects of rapamycin.
    Relation: CANCER RESEARCH 65(5):1961-1972
    Appears in Collections:[生物科技學系] 期刊論文

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