title: Integrity of p53 associated pathways determines induction of apoptosis of tumor cells resistant to Aurora-A kinase inhibitors.
abstract: We have previously shown that mammary tumorigenesis in MMTV-Aurora-A mice is further enhanced when p53 is inactivated, demonstrating that integrity of p53 pathway determines phenotypes induced by this oncogenic kinase. In this study, we investigated the roles of genes involved in p53 pathway (p53, Puma, p21, Bax, and Chk2) in response to Aurora-A inhibitors, VX680 and MK-8745, and explored whether chemoresistant tumor cells would further undergo apoptosis with other therapeutic agents. Isogenic HCT116 cell lines were treated with VX680 or MK-8745. Cell cycle analysis, apoptosis, and tumorigenesity were studied. Chemoresistant cells were recovered from xenograft, and further induction of apoptosis was studied. Induction of apoptosis and aneuploidy with VX680 is much stronger than MK-8745. Xenograft assay indicates that tumor growth of HCT116 and HCT116 p53(-) cells are strongly inhibited by VX680, while that of other cell types are similarly inhibited by two compounds. Among the established cell lines recovered from xenografts, MK-8745-resistant clones contain elevated phosphorylation of mTOR and Akt. When further treated with inhibitors of both mTOR and Akt, those cells undergo apoptosis. These results indicate that p53-associated pathway plays a crucial role in regulating growth inhibition of tumor cells when treated with Aurora-A inhibitors. Combined treatment with Akt/mTOR inhibitors can further induce apoptosis of Aurora-A tumors.
authors: Department of Medicine, National University of Health Sciences, Pritzker School of Medicine, The University of Chicago, Evanston, Illinois, United States of America.
authors: Yoshimi
authors: Y
authors: Shionome
authors: Li
authors: L
authors: Yan
authors: Song
authors: S
authors: Liu
authors: Toshiaki
authors: T
authors: Saeki
authors: Toru
authors: T
authors: Ouchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D064127:Aurora Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C574019:MK-8745; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576918:Aurka protein, mouse
references: Drug Discov Today. 2011 Mar;16(5-6):260-9
references: 21147253
references: Cell. 2012 Apr 13;149(2):274-93
references: 22500797
references: Leukemia. 2011 Feb;25(2):348-58
references: 21052088
references: Oncotarget. 2011 Dec;2(12):935-47
references: 22249213
references: Clin Cancer Res. 2003 Mar;9(3):991-7
references: 12631597
references: Br J Pharmacol. 2012 Jun;166(3):858-76
references: 22250956
references: Biochim Biophys Acta. 2011 Apr;1813(4):521-31
references: 21195116
references: Science. 2000 Nov 3;290(5493):989-92
references: 11062132
references: Cell Cycle. 2012 Feb 15;11(4):807-17
references: 22293494
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1931-6
references: 12574499
references: Expert Opin Investig Drugs. 2012 Mar;21(3):383-93
references: 22242557
references: Nat Genet. 1998 Oct;20(2):189-93
references: 9771714
references: EMBO J. 1998 Jun 1;17(11):3052-65
references: 9606188
references: J Natl Cancer Inst. 2002 Sep 4;94(17):1320-9
references: 12208897
references: Expert Opin Investig Drugs. 2009 Apr;18(4):379-98
references: 19335272
references: Expert Opin Drug Discov. 2011 Mar;6(3):291-307
references: 21556291
references: Clin Cancer Res. 2003 Apr;9(4):1420-6
references: 12684414
references: Int J Cancer. 2006 Nov 15;119(10):2304-12
references: 16894566
references: Clin Cancer Res. 2005 Mar 1;11(5):1827-34
references: 15756006
references: Science. 1998 Nov 20;282(5393):1497-501
references: 9822382
references: Nat Med. 2004 Mar;10(3):262-7
references: 14981513
references: J Biol Chem. 2003 Jun 6;278(23):20475-9
references: 12654917
references: Oncogene. 2006 Nov 16;25(54):7148-58
references: 16715125
references: Cancer Res. 2001 Mar 1;61(5):2212-9
references: 11280789
references: Curr Opin Cell Biol. 2011 Dec;23(6):744-55
references: 21963299
references: Cancer Res. 1999 May 1;59(9):2041-4
references: 10232583
references: Int J Biol Sci. 2009 Jun 19;5(5):444-50
references: 19564927
references: Biochim Biophys Acta. 2011 Apr;1813(4):508-20
references: 21146563
references: Cancer Res. 2007 Nov 1;67(21):10436-44
references: 17974987