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    Please use this identifier to cite or link to this item: http://asiair.asia.edu.tw/ir/handle/310904400/8327

    Title: Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer
    Authors: Ding, QQ (Ding, Qingqing);Huo, LF (Huo, Longfei);Yang, JY (Yang, Jer-Yen);Xia, WY (Xia, Weiya);Wei, YK (Wei, Yongkun);Liao, Y (Liao, Yong);Chang, CJ (Chang, Chun-Ju);Yang, Y (Yang, Yan);Lai, CC (Lai, Chien-Chen);Lee, DF (Lee, Dung-Fang);Yen, CJ (Yen, Chia-Jui);Chen, YJR (Chen, Yun-Ju Rita);Hsu, JM (Hsu, Jung-Mao);Kuo, HP (Kuo, Hsu-Ping);Lin, CY (Lin, Chun-Yi);Tsai, FJ (Tsai, Fuu-Jen);Li, LY (Li, Long-Yuan);Tsai, CH (Tsai, Chang-Hai);Hung, MC (Hung, Mien-Chie)
    Contributors: Department of Biotechnology
    Date: 2008-08
    Issue Date: 2010-03-26 10:29:50 (UTC+8)
    Publisher: Asia University
    Abstract: Myeloid cell leukemia-1 (Mcl-1), a Bel-2-like antiapoptotic protein, plays a role in cell immortalization and chemoresistance in a number of human malignancies. A peptidylprolyl cis/trans isomerase, Pinl is involved in many cellular events, such as cell cycle progression, cell proliferation, and differentiation through isomerizing prophosphorylated substrates. It has been reported that down-regulation of Pint induces apoptosis, and that Erk phosphorylates and upregulates Mcl-1; however, the underlying mechanisms for the two phenomena are not clear yet. Here, we showed that Pin I stabilizes Mcl-1, which is required for Mcl-I posphorylation by Erk. First, we found expression of Mcl-1 and Not were positively correlated and associated with poor survival in human breast cancer. We then showed that Erk could phosphorylate Mcl-1 at two consensus residues, Thr 92 and 163, which is required for the association of Mcl-1 and Pin 1, resulting in stabilization of Mcl-I. Moreover, Not is also required for the up-regulation of Mcl-I by Erk activation. Based on this newly identified mechanism of Mcl-1 stabilization, two strategies were used to overcome Mcl-1-mediated chemoresistance: inhibiting Erk by Sorafenib, an approved clinical anticancer drug, or knocking down Pinl by using a SiRNA technique. In conclusion, the current report not only unravels a novel mechanism to link Erk/Pinl pathway and Mcl-1-mediated chemoresistance but also provides a plausible combination therapy, Taxol (Paclitaxel) plus Sorafenib, which was shown to be effective in killing breast cancer cells.
    Relation: CANCER RESEARCH, 68 (15): 6109-6117
    Appears in Collections:[生物科技學系] 期刊論文

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