Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation.
The novel concept of anticancer treatment termed "G(2) checkpoint abrogation" aims to target p53-deficient tumor cells and is currently explored in clinical trials. The anticancer drug UCN-01 is used to abrogate a DNA damage-induced G(2) cell cycle arrest leading to mitotic entry and subsequent cell death, which is poorly defined as "mitotic cell death" or "mitotic catastrophe." We show here that UCN-01 treatment results in a mitotic arrest that requires an active mitotic spindle checkpoint, involving the function of Mad2, Bub1, BubR1, Mps1, Aurora B, and survivin. During the mitotic arrest, hallmark parameters of the mitochondria-associated apoptosis pathway become activated. Interestingly, this apoptotic response requires the spindle checkpoint protein Mad2, suggesting a proapoptotic function for Mad2. However, although survivin and Aurora B are also required for the mitotic arrest, both proteins are part of an antiapoptotic pathway that restrains the UCN-01-induced apoptosis by promoting hyperphosphorylation of Bcl-2 and by inhibiting the activation of Bax. Consequently, inhibition of the antiapoptotic pathway by genetic ablation of survivin or by pharmacologic inhibitors of Aurora B or cyclin-dependent kinase 1 lead to a significant enhancement of apoptosis and therefore act synergistically with UCN-01. Thus, by defining the mechanism of cell death on G(2) checkpoint abrogation we show a highly improved strategy for an anticancer treatment by the combined use of UCN-01 with abrogators of the survivin/Aurora B-dependent antiapoptotic pathway that retains the selectivity for p53-defective cancer cells.
Vogel
Celia
C
Institute for Molecular Biology and Tumor Research, Philipps University of Marburg, Emil-Mannkopff-Strasse 2, D-35037 Marburg, Germany.
Hager
Christian
C
Bastians
Holger
H
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D016195:G2 Phase / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins / Q000502:physiology; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077022:Survivin
C107489:BIRC5 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000077022:Survivin; C054852:7-hydroxystaurosporine; D004317:Doxorubicin; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D019311:Staurosporine