title: Axin1 expression facilitates cell death induced by aurora kinase inhibition through PARP activation.
abstract: Axin, a negative regulator of Wnt signaling, participates in apoptosis, and Axin1 localizes to centrosomes and mitotic spindles, which requires Aurora kinase activity. In this study, Aurora inhibition of Axin1-expressing cells (L-Axin) produced polyploid cells, which died within 48 h posttreatment, whereas Axin2-expressing cells (L-Axin2) survived the same period. These cell death events showed apoptotic signs, such as chromatin condensation and increased sub-G1 populations, as well as cell membrane rupture. Further analysis showed that Aurora kinase inhibitor (AKI) treatment of L-Axin cells induced poly(ADP-ribose) polymerase (PARP) activation, which increased the poly(ADP-ribosyl)ation of cellular proteins and reduced cellular ATP content. PARP inhibition reduced a proportion of dead cells, suggesting PARP involvement in AKI-induced cell death. Also, AKI treatment of L-Axin cells induced mitochondrial apoptosis-inducing factor (AIF) release, but not mitochondrial cytochrome c release or caspase-3 activation. Knockdown of AIF attenuated AKI-induced cell death in L-Axin cells. Thus, our results suggest that Axin1 expression renders L929 cells sensitive to Aurora inhibition-induced cell death in a PARP- and AIF-dependent manner.
authors.affiliation: Laboratory of Cell Biology, Department of Microbiology and Bank for Pathogenic Virus, College of Medicine, Korea University, Seoul 136-705, Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Choi
authors.forename: Shi-Mun
authors.initials: SM
authors.lastname: Kim
authors.forename: Ki-Joon
authors.initials: KJ
authors.lastname: Song
authors.forename: Jae-Myun
authors.initials: JM
authors.lastname: Lee
authors.forename: Sun-Ho
authors.initials: SH
authors.lastname: Kee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D064127:Aurora Kinases; D060466:Axin Protein / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D059008:Time-Lapse Imaging
chemical_list: D051033:Apoptosis Inducing Factor; D060466:Axin Protein; C555452:Axin1 protein, mouse; C111729:Axin2 protein, mouse; C494830:AIFM1 protein, mouse; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases