☆ 4.6 Article

Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis

ONCOGENESIS (2017)

Journal

ONCOGENESIS

Volume 6, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP

DOI: 10.1038/oncsis.2016.80

Keywords

Funding

National Basic Research Program of China (973 Program) [2012CB967000]
National Natural Science Foundation of China [81130040, 81573025, 81402445]
National High Technology Research and Development Program of China (863 Program) [2015AA020926]
Special Support Program for Training High Level Talents in Guangdong Province [2014TQ01R138]
Fundamental Research Funds for the Central Universities [15ykjc20c]
Breast Cancer Campaign [2012 May PR070, 2012NovemberPhD016]
Cancer Research UK (CRUK) [A12011]
Biotechnology and Biological Sciences Research Council [BBS/B/03785] Funding Source: researchfish
Cancer Research UK [12011] Funding Source: researchfish
Engineering and Physical Sciences Research Council [1234732] Funding Source: researchfish
Medical Research Council [MR/N012097/1] Funding Source: researchfish
MRC [MR/N012097/1] Funding Source: UKRI

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Abstract

Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies. However, little is known about its role in gastric cancer prognosis and genotoxic resistance. Here we found that AURKA was highly overexpressed in gastric cancer and inversely correlated with disease prognosis. Overexpression of AURKA exacerbated gastric cancer drug resistance through upregulating the expression of the anti-apoptotic protein Survivin. Conversely, we demonstrated that AURKA depletion caused a decrease in Survivin protein levels by increasing its ubiquitylation and degradation. Mass spectrometric analysis revealed that upon AURKA depletion, Survivin bound to the FBXL7 E3 ubiquitin ligase, which induced ubiquitin-proteasome degradation of Survivin. In addition, we showed that AURKA regulated FBXL7 both at the levels of transcription and translation. Moreover, proteomic analysis of nuclear AURKA-interacting proteins identified Forkhead box protein P1 (FOXP1). We next showed that AURKA was required for FBXL7 transcription and that AURKA negatively regulated FOXP1-mediated FBXL7 expression. The physiological relevance of the regulation of Survivin by AURKA through the FOXP1-FBXL7 axis was further underscored by the significant positive correlations between AURKA and Survivin expression in gastric cancer patient samples. Moreover, the AURKA depletion or kinase inhibition-induced apoptotic cell death could be reversed by Survivin ectopic overexpression, further supporting that AURKA regulated Survivin to enhance drug resistance. In agreement, inhibition of AURKA synergistically enhanced the cytotoxic effect of DNA-damaging agents in cancer cells by suppressing Survivin expression. Taken together, our data suggest that AURKA restricts Survivin ubiquitylation and degradation in gastric cancer to promote drug resistance and hence the AURKA-Survivin axis can be targeted to promote the efficacy of DNA-damaging agents in gastric cancer.

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Selective targeting of Aurora kinase B over A: Uncovering the structural basis for inhibitor specificity through molecular dynamics simulations

Dong Zhao, Antal H. Kovacs, Michael Campbell, Wely Floriano, Jinqiang Hou

Summary: In this study, the selective binding mechanism of Barasertib, a ligand with high selectivity for Aurora kinase B over A, was investigated through molecular dynamics simulations and binding free energy analyses. The results showed that the hinge residue Arg159 in Aurora kinase B played a crucial role in Barasertib binding, and the binding interactions at the hydrophobic back pocket were important for the selectivity. The insights into the structural determinants of subtype selectivity will contribute to the development of selective Aurora kinase B inhibitors for cancer therapy.

JOURNAL OF MOLECULAR STRUCTURE (2023)