Axin1 expression facilitates cell death induced by aurora kinase inhibition through PARP activation

• Published in: Journal of cellular biochemistry 2011-09, Vol.112 (9), p.2392-2402
• Main Authors: Choi, Eun-Jin, Kim, Shi-Mun, Song, Ki-Joon, Lee, Jae-Myun, Kee, Sun-Ho
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; AIF; Animals; Apoptosis; Apoptosis Inducing Factor - genetics; Apoptosis Inducing Factor - metabolism; Aurora kinase; Aurora Kinases; Axin; Axin Protein - metabolism; Cell death; Cell Line; Cell Membrane - metabolism; Cell Membrane - physiology; Enzyme Activation; Mice; Mitochondria - metabolism; PARP; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; RNA Interference; Time-Lapse Imaging
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.23162

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. J. Cell. Biochem. 112: 2392–2402, 2011. © 2011 Wiley‐Liss, Inc.