Potentiation of kinesin spindle protein inhibitor-induced cell death by modulation of mitochondrial and death receptor apoptotic pathways.
Targeting the mitotic motor kinesin kinesin spindle protein (KSP) is a new strategy for cancer therapy. We have examined the molecular events induced by KSP inhibition and explored possible mechanisms of resistance and sensitization of tumor cells to KSP inhibitors. We found that KSP inhibition induced cell death primarily via activation of the mitochondrial death pathway. In HeLa cells, inhibition of KSP by small-molecule inhibitor monastrol resulted in mitotic arrest and rapid caspase activation. BclXL phosphorylation and loss of mitochondrial membrane potential was detected before significant caspase activation, which was required to trigger the subsequent apoptotic pathway. In A549 cells, however, KSP inhibition did not induce mitochondrial damage, significant caspase activity, or cell death. A549 cells aberrantly exited mitosis, following a prolonged drug-induced arrest, and arrested in a G(1)-like state with 4N DNA content in a p53-dependent manner. Overexpression of BclXL provided a protective mechanism, and its depletion rescued the apoptotic response to monastrol. In addition, Fas receptor was up-regulated in A549 cells in response to monastrol. Treatment with Fas receptor agonists sensitized the cells to monastrol-induced cell death, following exit from mitosis. Thus, activation of the death receptor pathway offered another mechanism to enhance KSP inhibitor-induced apoptosis. This study has elucidated cellular responses induced by KSP inhibitors, and the results provide insights for a more effective cancer treatment with these agents.
Vijapurkar
Ulka
U
Schering-Plough Biopharma, Palo Alto, CA, USA.
Wang
Wei
W
Herbst
Ronald
R
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D013871:Thiones / Q000494:pharmacology*; D051020:bcl-X Protein / Q000502:physiology; D019014:fas Receptor / Q000819:agonists / Q000502:physiology
D011743:Pyrimidines; D013871:Thiones; D051020:bcl-X Protein; D019014:fas Receptor; C400223:monastrol; D020169:Caspases; D016547:Kinesins