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    Please use this identifier to cite or link to this item: http://asiair.asia.edu.tw/ir/handle/310904400/4568

    Title: Down-regulation of Myeloid Cell Leukemia-1 through Inhibiting Erk/Pin 1 Pathway by Sorafenib Facilitates Chemosensitization in Breast Cancer
    Authors: Qingqing Ding;Longfei Huo;Jer-Yen Yang;Weiya Xia;Yongkun Wei;Yong Liao;Chun-Ju Chang;Yan Yang;Chien-Chen Lai;Dung-Fang Lee;Chia-Jui Yen;Yun-Ju Rita Chen;Jung-Mao Hsu;Hsu-Ping Kuo;Chun-Yi Lin;Fuu-Jen Tsai;Long-Yuan Li;Chang-Hai Tsai;Mien-Chie Hung
    Date: 2008-04
    Issue Date: 2009-11-27 13:56:51 (UTC+8)
    Publisher: Asia University
    Abstract: Myeloid cell leukemia-1 (Mcl-1), a Bcl-2?like antiapoptotic protein, plays a role in cell immortalization and chemoresistance in a number of human malignancies. A peptidyl-prolyl cis/trans isomerase, Pin1 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 Pin1 induces apoptosis, and that Erk phosphorylates and up-regulates Mcl-1; however, the underlying mechanisms for the two phenomena are not clear yet. Here, we showed that Pin 1 stabilizes Mcl-1, which is required for Mcl-1 posphorylation by Erk. First, we found expression of Mcl-1 and Pin1 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 Pin1, resulting in stabilization of Mcl-1. Moreover, Pin1 is also required for the up-regulation of Mcl-1 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 Pin1 by using a SiRNA technique. In conclusion, the current report not only unravels a novel mechanism to link Erk/Pin1 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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