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Down-regulation of Myeloid Cell Leukemia-1 through Inhibiting Erk/Pin 1 Pathway by Sorafenib Facilitates Chemosensitization in Breast Cancer

¹ Department of Molecular and Cellular Oncology, ² Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, and ³ Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas; ⁴ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and ⁵ China Medical University and Hospital, ⁶ Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital; and ⁷ Asia University, Taichung, Taiwan

Requests for reprints: Mien-Chie Hung, Department of Molecular and Cellular Oncology, Unit 108, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3668; Fax: 713-794-3270; E-mail: mhung{at}mdanderson.org.

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. [Cancer Res 2008;68(15):6109–17]