Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer.
Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer.
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DOI：
10.1158/0008-5472.can-08-0579
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Hung MC
中科院分区：
文献类型：
--
作者：
Ding Q;Huo L;Yang JY;Xia W;Wei Y;Liao Y;Chang CJ;Yang Y;Lai CC;Lee DF;Yen CJ;Chen YJ;Hsu JM;Kuo HP;Lin CY;Tsai FJ;Li LY;Tsai CH;Hung MC
髓样细胞白血病-1（Mcl-1）是一种Bcl-2样抗凋亡蛋白，在许多人类恶性肿瘤的细胞永生化和化疗耐药性中发挥作用。Pin 1是一种肽基脯氨酰顺式/反式异构酶，通过异构化前磷酸化底物参与许多细胞事件，如细胞周期进展、细胞增殖和分化。已有研究表明Pin 1的下调可诱导细胞凋亡，Erk可磷酸化并上调Mcl-1，但这两种现象的机制尚不清楚。在这里，我们表明Pin 1稳定了Mcl-1，这是Erk对Mcl-1磷酸化所必需的。首先，我们发现Mcl-1和Pin 1的表达正相关，并且与人类乳腺癌的生存率低相关。然后，我们发现Erk可以在两个共有残基Thr 92和163处磷酸化Mcl-1，这是Mcl-1和Pin 1结合所必需的，从而使Mcl-1稳定。此外，Pin 1也是通过Erk激活上调Mcl-1所必需的。基于这种新发现的Mcl-1稳定机制，使用两种策略来克服Mcl-1介导的化学抗性：通过批准的临床抗癌药物索拉非尼抑制Erk，或通过使用SiRNA技术敲低Pin 1。总之，目前的报告不仅揭示了一种新的机制，连接Erk/Pin 1通路和Mcl-1介导的化疗耐药性，但也提供了一个合理的联合治疗，紫杉醇（紫杉醇）加索拉非尼，这是有效地杀死乳腺癌细胞。
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.