Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathway

Minglun Li , Anke Jung , Ute Ganswindt , Patrizia Marini , Anna Friedl , Peter T. Daniel , Kirsten Lauber , Verena Jendrossek , Claus Belka

ZM447439 (ZM) is a potent and selective inhibitor of aurora-A and -B kinase with putative anti-tumoral activity. Inhibitors of aurora kinases were shown to induce apoptosis and . To investigate the underlying mechanisms, cell death pathways triggered by ZM was analysed in HCT-116 colorectal cancer cells. Through correlation of polyploidization and apoptosis in different knockout cells, the interrelation of these cellular responses to ZM was investigated. ZM induced apoptosis in a concentration- and time-dependent manner. ZM-induced apoptosis was associated with an upregulation of p53, breakdown of the mitochondrial membrane potential (ΔΨm) and activation of caspase-3. To precisely define key components for ZM-induced apoptosis, knoutout cells lacking p53, Bak, Bax or both Bak and Bax were used. Lack of p53 reduced ZM-induced apoptosis and breakdown of ΔΨm, while lack of Bak, Bax or both almost completely inhibited apoptosis and breakdown of ΔΨm. Since no difference in apoptosis induction was detectable between HCT-116 cells lacking Bak, Bax or both, apoptosis induction depended non-redundantly on both Bak and Bax. Phenomenally, ZM induced notable polyploidization in all examined cells, especially in p53-/- cells. A correlation between polyploidization and apoptosis was observed in wild-type, and also in p53-/- cells, albeit with a modest extent of apoptosis. Moreover, in Bak-/-, Bax-/- and Bak/Bax-/- cells apoptosis was totally inhibited in spite of the strongest polyploidization, suggesting apoptosis may be a secondary event following polyploidization in HCT-116 cells. Thus ZM-induced apoptosis depends not only on polyploidization, but also on the intracellular apoptotic signaling.

Mots clés: Aurora kinase inhibitor ZM447439; Apoptosis; Mitochondrial pathway; Colorectal tumor cells; Polyploidization

Minglun Li, Anke Jung, Ute Ganswindt, Patrizia Marini, Anna Friedl, et al.. Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathway. Biochemical Pharmacology, 2009, 79 (2), pp.122. ⟨10.1016/j.bcp.2009.08.011⟩. ⟨hal-00535825⟩