This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ding, Q. Articles by Hung, M.-C. Search for Related Content PubMed PubMed Citation Articles by Ding, Q. Articles by Hung, M.-C.

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]

This article has been cited by other articles:

				D.-L. Ou, Y.-C. Shen, J.-D. Liang, J.-Y. Liou, S.-L. Yu, H.-H. Fan, D.-S. Wang, Y.-S. Lu, C. Hsu, and A.-L. Cheng Induction of Bim Expression Contributes to the Antitumor Synergy Between Sorafenib and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Inhibitor CI-1040 in Hepatocellular Carcinoma Clin. Cancer Res., September 15, 2009; 15(18): 5820 - 5828. [Abstract] [Full Text] [PDF]

				H.-L. Sun, A.-C. Tsai, S.-L. Pan, Q. Ding, H. Yamaguchi, C.-N. Lin, M.-C. Hung, and C.-M. Teng EPOX Inhibits Angiogenesis by Degradation of Mcl-1 through ERK Inactivation Clin. Cancer Res., August 1, 2009; 15(15): 4904 - 4914. [Abstract] [Full Text] [PDF]