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J. Biol. Chem., Vol. 281, Issue 26, 18090-18097, June 30, 2006

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Inhibition of the Mitotic Kinesin Eg5 Up-regulates Hsp70 through the Phosphatidylinositol 3-Kinase/Akt Pathway in Multiple Myeloma Cells^*

Min Liu, Ritu Aneja, Chunyong Liu, Lei Sun, Jinmin Gao, Hongxia Wang, Jin-Tang Dong^¶, Vasiliki Sarli^||, Athanassios Giannis^||, Harish C. Joshi, and Jun Zhou¹

From the Department of Genetics and Cell Biology and Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, Tianjin 300071, China, the Department of Cell Biology and the ^¶Department of Hematology and Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, and the ^||Institute for Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany

The microtubule-dependent motor protein Eg5 plays a critical role in spindle assembly and maintenance in mitosis. Herein we show that the suppression of Eg5 by a specific inhibitor arrested mitosis, induced apoptosis, and up-regulated Hsp70 in human multiple myeloma cells. Mechanistically, Hsp70 induction occurred at the transcriptional level via a cis-regulatory DNA element in Hsp70 promoter and was mediated by the phosphatidylinositol 3-kinase/Akt pathway. Eg5 inhibitor-mediated Hsp70 up-regulation is cytoprotective because blocking Hsp70 induction directly by antisense or small interfering RNA or indirectly by inhibiting the phosphatidylinositol 3-kinase/Akt pathway significantly increased Eg5 inhibitor-induced apoptosis. Furthermore, a farnesyltransferase inhibitor interacted synergistically with the Eg5 inhibitor in inducing apoptosis through disrupting the Akt/Hsp70 signaling axis. These findings provide the first evidence for Eg5 inhibitor activity in hematologic malignancy and identify Hsp70 up-regulation as a critical mechanism responsible for modulating myeloma cell sensitivity to Eg5 inhibitors. In addition, these findings suggest that a combination of Eg5 inhibitors with agents abrogating Hsp70 induction would be useful for myeloma therapy in the clinic.

Received for publication, February 10, 2006 , and in revised form, April 19, 2006.

^* This work was supported by Nankai University (to J. Z. and J. T. D.) and by grants from the National Institutes of Health (to H. C. J.) and the European Commission (to V. S. and A. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Rd., Tianjin 300071, China. Tel. and Fax: 86-22-2350-4946; E-mail: junzhou{at}nankai.edu.cn.

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