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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
CITATION STYLE
Liu, M., Aneja, R., Liu, C., Sun, L., Gao, J., Wang, H., … Zhou, J. (2006). Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells. Journal of Biological Chemistry, 281(26), 18090–18097. https://doi.org/10.1074/jbc.M601324200
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