p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells.
We previously showed that AZD1152-HQPA, the inhibitor of Aurora B kinase potently induced growth arrest and apoptosis of various types of human leukemia cells including MV4-11 acute myelogenous leukemia (AML) cells, although the molecular mechanisms by which this class of kinase inhibitors induces apoptosis remain to be fully elucidated. We have recently established the MV4-11 subline, designated as MV4-11 TP53 R248W, which possesses transcriptionally inactive R248W mutation in the TP53 gene. MV4-11 TP53 R248W cells were relatively resistant to AZD1152-HQPA-mediated growth arrest, as measured by MTT and clonogenic assays. AZD1152-HQPA (10-100 nM, 48 h) strikingly induced apoptosis of MV4-11 cells, as assessed by Annexin V binding, loss of mitochondrial outer membrane potential, and activation of caspase cascade, in parallel with up-regulation of p53 and its target molecules Bax and Noxa. Notably, AZD1152-HQPA (10-100 nM, 48 h) induced polyploidy rather than apoptosis in MV4-11 TP53 R248W cells. The polyploid cells were eventually eliminated via apoptosis at later time period (72-120 h) in association with up-regulation of p73. Taken together, p53 plays an important role in AZD1152-HQPA-induced growth arrest and early onset of apoptosis in AML cells. P73 may mediate the late onset of apoptosis to eliminate the polyploid cells caused by the inhibitor of Aurora B kinase.
Ikezoe
Takayuki
T
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan. ikezoet@kochi-u.ac.jp
Yang
Jing
J
Nishioka
Chie
C
Yokoyama
Akihito
A
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C531556:AZD 1152-HQPA; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases