title: Involvement of caspase-2 activation in aurora kinase inhibitor-induced cell death in axin-expressing L929 cells.
abstract: Axin is a multifunctional protein that participates in many cellular events including Wnt signaling and cell fate determination. Aurora kinase inhibitor (AKI)-induced cell death and cell membrane rupture is facilitated in L929 cells expressing axin (L-axin cells) through the activation of poly ADP-ribose polymerase (PARP). We observed that caspase-2 activity is required for AKI-induced cell death. Inhibition of caspase-2 activity suppressed AKI-induced PARP activation and mitochondrial dysfunction, resulting in a decrease in AKI-induced cell death. When an axin mutant deleted for the glycogen synthase kinase 3β (GSK3β)-binding domain was expressed in L929 cells (L-ΔGSK cells), AKI-induced caspase-2 activation and cell death decreased. AKI treatment reduced the expression of a 32-kDa caspase-2 splicing variant (caspase-2S) in most L-axin cells, but not in L-ΔGSK cells. These results suggest that AKI-induced caspase-2 activation in L-axin cells might be due to a decrease in the expression of caspase-2S, which inhibits caspase-2 activity. In addition, AKI treatment failed to activate caspase-8 and treatment with necrostatin inhibited AKI-induced cell death in L-axin cells, suggesting that the absence of caspase-8 activation might favor necrotic cell death. Axin expression may facilitate AKI-induced caspase-2 activation followed by activation of PARP and initiation of the necrotic cell death pathway.
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: Jee-Hye
authors.initials: JH
authors.lastname: Shin
authors.forename: Sewon
authors.initials: S
authors.lastname: Kim
authors.forename: Ki-Joon
authors.initials: KJ
authors.lastname: Song
authors.forename: Sun-Ho
authors.initials: SH
authors.lastname: Kee
mesh_terms: D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060466:Axin Protein / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation; D051379:Mice; D009336:Necrosis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D060466:Axin Protein; D061945:Caspase Inhibitors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D064127:Aurora Kinases; D053143:Caspase 2; D053181:Caspase 8