P21-activated kinase 7 mediates cisplatin-resistance of esophageal squamous carcinoma cells with Aurora-A overexpression.

Shun He,Wei Zhang,Shangbin Yang,Hongxia Zhu,Shuang Yan,Mei Liu,Qing Xu,Ningzhi Xu,Chenfei Hu,Zaozao Wang,Min Feng,Lechuang Chen

doi:10.1371/journal.pone.0113989

Abstract

Aurora-A overexpression is common in various types of cancers and has been shown to be involved in tumorigenesis through different signaling pathways, yet how the deregulation affects cancer therapeutics remains elusive. Here we showed that overexpression of Aurora-A rendered esophageal cancer cells resistance to cisplatin (CDDP) by inhibiting apoptosis. By using an apoptosis array, we identified a downstream gene, p21-activated kinase 7 (PAK7). PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels. Importantly, the expression levels of Aurora-A and PAK7 were correlated in ESCC primary samples. Chromatin immunoprecipitation (ChIP) assay revealed that binding of E2F1 to the promoter of PAK7 was significantly enhanced upon Aurora-A activation, and knockdown of transcription factor E2F1 decreased PAK7 expression, suggesting that Aurora-A regulated PAK7 through E2F1. Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP. Our data suggest that PAK7 may serve as an attractive candidate for therapeutics in ESCC patients with Aurora-A abnormality.

Highlights

Aurora-A, a member of the Aurora kinase family, is an evolutionally conserved serine/threonine kinase that plays a vital role in maintaining proper chromosome segregation and cytokinesis during mitosis [1]
In this study we demonstrated that Aurora-A overexpression dramatically decreased the sensitivity of the esophageal cancer cells to the chemotherapy drug CDDP by inhibiting cell apoptosis
To better understand the role of Aurora-A in esophageal cancers, we established Aurora-A overexpression cell line in EC9706 and explored how the high levels of Aurora-A would affect the response of the cancer cells to chemotherapeutic drugs

Summary

Introduction

Aurora-A, a member of the Aurora kinase family, is an evolutionally conserved serine/threonine kinase that plays a vital role in maintaining proper chromosome segregation and cytokinesis during mitosis [1]. It is reported that Aurora-A overexpression positively correlates with cancer stages in hepatocellular carcinoma, ovarian cancer, bladder cancer and head and neck cancer [3,4,5,6]. In the latter two cancer types, the aberrant expression of Aurora-A was often found to be associated with metastasis. It’s reported that the Aurora-A inhibitor could enhance cisplatin (CDDP) -induced cell death in esophageal adenocarcinoma cells [12], it’s of great importance to examine how the abnormal expression of Aurora-A affects the treatment of these cancer patients

Methods

Results

Conclusion