Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer

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

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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.

Original languageEnglish
Pages (from-to)6109-6117
Number of pages9
JournalCancer Research
Volume68
Issue number15
DOIs
Publication statusPublished - 2008 Aug 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Ding, Q., Huo, L., Yang, J. Y., Xia, W., Wei, Y., Liao, Y., Chang, C. J., Yang, Y., Lai, C. C., Lee, D. F., Yen, C. J., Chen, Y. J. R., Hsu, J. M., Kuo, H. P., Lin, C. Y., Tsai, F. J., Li, L. Y., Tsai, C. H., & Hung, M. C. (2008). Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Research, 68(15), 6109-6117. https://doi.org/10.1158/0008-5472.CAN-08-0579