Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells

The Journal of Biological Chemistry
Min LiuJun Zhou

Abstract

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 us...Continue Reading

References

Jul 1, 1992·The Journal of Cell Biology·D M RoofM D Rose
Jan 1, 1986·The American Journal of Physiology·J R Subjeck, T T Shyy
Nov 1, 1993·The Journal of Cell Biology·M M HeckL S Goldstein
Aug 10, 2000·Nature Cell Biology·A SalehE S Alnemri
Feb 24, 2001·Annals of the New York Academy of Sciences·J NylandstedM Jäättelä
Mar 30, 2001·The Journal of Biological Chemistry·N R MadamanchiM S Runge
Sep 5, 2001·Nature Cell Biology·L RavagnanG Kroemer
Aug 21, 2002·Journal of Cell Science·Jun ZhouHarish C Joshi
Oct 23, 2002·Molecular and Cellular Biology·Hee-Sae ParkEui-Ju Choi
Jan 18, 2003·Biological Chemistry·Mathias GehrmannGabriele Multhoff
Jun 5, 2003·Angewandte Chemie·Srinivas HothaTarun M Kapoor
Jul 23, 2003·Trends in Pharmacological Sciences·Paula M ChecchiHarish C Joshi
Apr 2, 2004·Nature Reviews. Cancer·Mary Ann Jordan, Leslie Wilson
May 6, 2004·Cancer Research·Roman SakowiczKenneth W Wood
Jan 18, 2005·The Journal of Biological Chemistry·Adam I MarcusParaskevi Giannakakou
Feb 22, 2005·Current Medicinal Chemistry. Anti-cancer Agents·Jun Zhou, Paraskevi Giannakakou
Mar 24, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hyo-Soo KimKenneth Walsh
May 25, 2005·Chembiochem : a European Journal of Chemical Biology·Michael GartnerAthanassios Giannis
Aug 6, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hong Pyo KimAugustine M K Choi

❮ Previous
Next ❯

Citations

May 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Lei SunJun Zhou
Jun 22, 2007·Anti-cancer Drugs·Maricarmen D Planas-Silva, Irina S Filatova
Mar 5, 2014·The Journal of Clinical Investigation·Pascal BrouillardMiikka Vikkula
Jun 12, 2013·Cancer Letters·Leslie CalapreMel Ziman
Apr 17, 2013·Expert Opinion on Investigational Drugs·Michel D WissingHans Gelderblom
Jan 29, 2013·Toxicology and Applied Pharmacology·Ling-Huei YihHsiao-Hui Kuo
Apr 18, 2009·Toxicology and Applied Pharmacology·Yi-Chen WuLing-Huei Yih
Aug 21, 2008·Cell Motility and the Cytoskeleton·Irina TikhonenkoMichael P Koonce
Feb 27, 2013·Cancer Science·Xinran LiuKun Huang
Aug 21, 2013·Gene·Edward J WojcikSunyoung Kim
Mar 17, 2015·Medical Microbiology and Immunology·Emma Poole, John Sinclair
Jun 22, 2018·Thoracic Cancer·Min LiuJun Zhou
Jan 29, 2008·The Journal of Biological Chemistry·Jinmin GaoJun Zhou
May 18, 2016·Proceedings of the National Academy of Sciences of the United States of America·Stephen DiGiuseppeMartin J Sapp
Dec 3, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vasiliki Sarli, Athanassios Giannis
Oct 2, 2014·Cancer Research·Xinran LiuKun Huang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.