Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells.
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.
Liu
Min
M
Department of Genetics and Cell Biology and Key Laboratory of Bioactive Materials (Ministry of Education), College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Aneja
Ritu
R
Liu
Chunyong
C
Sun
Lei
L
Gao
Jinmin
J
Wang
Hongxia
H
Dong
Jin-Tang
JT
Sarli
Vasiliki
V
Giannis
Athanassios
A
Joshi
Harish C
HC
Zhou
Jun
J
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002867:Chromones; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D018840:HSP70 Heat-Shock Proteins; D016547:Kinesins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D034741:RNA, Small Interfering; C470243:KIF11 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one