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http://ir.cmu.edu.tw/ir/handle/310903500/7085
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| 題名: | Down-regulation of Myeloid Cell Leukemia-1 through Inhibiting Erk/Pin 1 Pathway by Sorafenib Facilitates Chemosensitization in Breast Cancer |
| 作者: | (Qingqing Ding);(Longfei Huo);(Jer-Yen Yang);(Weiya Xia,);(Yongkun Wei,);(Yong Liao,);(Chun-Ju Chang,);(Yan Yang,);賴建成(Chien-Chen Lai);(Dung-Fang Lee,);(Chia-Jui Yen,);(Yun-Ju Rita Chen,);(Jung-Mao Hsu,);(Hsu-Ping Kuo,);林俊毅(Chun-Yi Lin);蔡輔仁(Fuu-Jen Tsai);李龍緣(Long-Yuan Li);蔡長海(Chang-Hai Tsai);洪明奇(Mien-Chie Hung)* |
| 貢獻者: | 醫學院癌症生物學研究所;中國附醫院長室 |
| 日期: | 2008-08 |
| 上傳時間: | 2009-08-26 16:11:25 (UTC+8) |
| 摘要: | 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. |
| 關聯: | CANCER RESEARCH 68(15)6109~6117 |
| 顯示於類別: | [癌症生物學研究所] 期刊論文
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