Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells.
The mitotic Aurora kinases, including Aurora-A and Aurora- B, are attractive novel targets for anticancer therapy, and inhibitory drugs have been developed that are currently undergoing clinical trials. However, the molecular mechanisms how these drugs induce tumor cell death are poorly understood. We have addressed this question by comparing the requirements for an efficient induction of apoptosis in response to MLN8054, a selective inhibitor of Aurora-A, and the selective Aurora-B inhibitor ZM447439 in human colon carcinoma cells. By using various isogenic knockout as well as inducible colon carcinoma cell lines, we found that treatment with MLN8054 induces defects in mitotic spindle assembly, which causes a transient spindle checkpoint-dependent mitotic arrest. This cell cycle arrest is not maintained due to the activity of MLN8054 to override the spindle checkpoint. Subsequently, MLN8054-treated cells exit from mitosis and activate a p53-dependent postmitotic G(1) checkpoint, which subsequently induces p21 and Bax, leading to G(1) arrest followed by the induction of apoptosis. In contrast, inhibition of Aurora-B by ZM447439 also interferes with normal chromosome alignment during mitosis and overrides the mitotic spindle checkpoint but allows a subsequent endoreduplication, although ZM447439 potently activates the p53-dependent postmitotic G(1) checkpoint. Moreover, the ZM447439-induced endoreduplication is a prerequisite for the efficiency of the drug. Thus, our results obtained in human colon carcinoma cells indicate that although both Aurora kinase inhibitors are potent inducers of tumor cell death, the pathways leading to the induction of apoptosis in response to these drugs are distinct.
Kaestner
Phillip
P
Institute for Molecular Biology and Tumor Research, Philipps University Marburg, Marburg, Germany.
Stolz
Ailine
A
Bastians
Holger
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; C494827:Bax protein, mouse; D001549:Benzamides; D001552:Benzazepines; D050759:Cyclin-Dependent Kinase Inhibitor p21; C518940:MLN8054; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases