Abstract LB-97: Aurora kinase inhibition suppresses colon cancer cell growth through NF-κb-mediated PUMA induction.

Abstract

Abstract Aurora kinases are a group of highly conserved protein kinases that play a key role in mitosis. It has been shown that aurora kinases are overexpressed in a variety of tumors, and their overexpression contributes to aneuploidy in cancer cells. Inhibitors of aurora kinases have been developed and showed promises in recent studies. However, the mechanisms by which aurora kinase inhibitors suppress tumor cell growth have remained unclear. In this study, we found that ZM-447439, an aurora B inhibitor that has been tested in a number of preclinical studies, suppressed colon cancer cell growth by inducing apoptosis through PUMA, a p53 downstream target and a BH3-only Bcl-2 family protein. Treatment with ZM-447439 strongly induced PUMA in a variety of colon cancer cells irrespective of their p53 status. The induction of PUMA by ZM-447439 is mediated by IκB-dependent activation of NF-κB, which directly binds to the PUMA promoter to activate its transcription. Deficiency in PUMA abrogated ZM-447439-induced apoptosis and caspase activation, and rendered ZM-447439 resistance in vitro and in vivo. Furthermore, chemosensitization by ZM-447439 was also found to be PUMA-dependent. Together, these results demonstrate a key role of PUMA-dependent apoptosis in mediating the therapeutic effect of aurora kinase inhibition. They provide a rationale for manipulating the apoptotic machinery to improve sensitivity and overcome resistance to aurora kinase inhibitors. Citation Format: Jing Sun, Kan He, Jian Yu, Lin Zhang. Aurora kinase inhibition suppresses colon cancer cell growth through NF-κb-mediated PUMA induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-97. doi:10.1158/1538-7445.AM2013-LB-97