Aurora kinase A inhibition leads to p73-dependent apoptosis in p53-deficient cancer cells.
Aurora kinase A inhibition leads to p73-dependent apoptosis in p53-deficient cancer cells.
复制标题
Aurora激酶A抑制作用导致p53缺陷癌细胞的p73依赖性凋亡。
DOI：
10.1158/0008-5472.can-08-2658
复制
发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
El-Rifai, Wael
中科院分区：
文献类型：
--
作者：
Dar, Altaf A.;Belkhiri, Abbes;Ecsedy, Jeffrey;Zaika, Alexander;El-Rifai, Wael
We investigated the role of Aurora kinase A (AURKA) in regulating p73-dependent apoptosis utilizing p53-deficient cancer cell lines; H1299, TE7, and HCT116p53−/−. Overexpression of AURKA led to down-regulation of the TAp73-induced activation of the p53/p73-dependent luciferase reporter plasmid (pG13-luc). The reduction in the TAp73 transcription activity was confirmed by measuring the activity of luciferase reporters for p21/WAF1, and Puma. The siRNA knockdown of endogenous AURKA reversed these effects and Western blot analysis demonstrated a significant increase in the protein level of TAp73 and its downstream transcription targets; Puma, Noxa, and p21/WAF1. The co-expression of AURKA together with TAp73 inhibited the activation of the pG13-luc, Puma-luc, and p21/WAF1-luc reporter plasmids with reduction in the protein levels of TAp73 transcription targets. Treatment with AURKA-selective small molecule inhibitor, MLN8054 (Millennium Pharmaceuticals, Cambridge, MA) led to a significant increase in the activities of pG13-luc, Puma-luc, and p21/WAF1-luc reporter plasmids. This effect was accompanied by a significant increase in the mRNA and protein levels of several TAp73 transcription targets; p21/WAF1, PUMA, and NOXA. Flow cytometry cell cycle analysis, following MLN8054 treatment showed more than a two-fold increase in cell death. The apoptotic outcome was corroborated by showing an increase in cleaved caspase-3 protein levels by Western blot. Using TUNEL assay, we demonstrated that the expression of dominant-negative mutant TAp73 expression plasmid (p73DD) counteracted the MLN8054-induced cell death. Taken together, our results indicate that AURKA regulates TAp73-dependent apoptosis and highlight the potential of the AURKA inhibitor MLN8054 in treating cancers that are defective in p53 signaling.
