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

M Kamran,C-L Wang,Q Liu,E W-F Lam,S-S Lv,D Xu,Z-J Long,J Xu,B Liu

doi:10.1038/oncsis.2016.80

M Kamran, C-L Wang + Show 7 more

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https://doi.org/10.1038/oncsis.2016.80

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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.

Highlights

Gastric cancer is one of the most common cancers with high incidence of disease-related deaths and poor prognosis.[1]Currently, surgical resection and chemotherapy are the most effective treatments
We studied the expression of Aurora kinase A (AURKA) protein in a large cohort of chemistry of 62 pairs of gastric cancer specimens and found that AURKA expression was positively correlated with Survivin expression (r = 0.402; P o 0.01; Figure 2d; Supplementary Table 3)
Considering that co-overexpression of AURKA and Survivin was associated with poor prognosis of gastric carcinomas, we assessed the effect of Survivin expression on drug sensitivity

Summary

Introduction

Gastric cancer is one of the most common cancers with high incidence of disease-related deaths and poor prognosis.[1]Currently, surgical resection and chemotherapy are the most effective treatments. Patients with locally advanced disease respond poorly to chemotherapeutic modalities, reflecting an inherent refractive mechanism against drug-induced cell death.[2] Several previous reports have attempted to explore the molecular markers that drive drug resistance. These proposed markers and signatures, including PI3K/Akt, NFκB, inhibitors of apoptosis (IAPs) and Bcl-2 family proteins, are highly expressed in gastric cancer and associated with resistance to chemotherapyinduced cell death.[3,4]. Aurora kinases were first identified in Drosophila as key players in chromosomal segregation.[5] Subsequently, orthologues were discovered in humans and implicated in the control of distinct and unrelated aspects of mitosis.

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