Aurora-A Induces Chemoresistance Through Activation of the AKT/mTOR Pathway in Endometrial Cancer.

Jun Wu,Ziyun Cheng,Tao Liu,Chan Wu,Huaijun Zhou,Jian Fu,Xiaofeng Xu,Qian Yang,Kaiyue Wang,Xiangyi Kong,Guijun Yan

doi:10.3389/fonc.2019.00422

Abstract

Endometrial cancer (EC) is the most common gynecological tumor all over the world, and advanced/metastatic EC remains a malignancy with poor survival outcome due to highly resistant to conventional chemotherapeutic treatment. Here, we report that Aurora-A, a serine-threonine kinase, plays a vital role in chemoresistance of EC. Aurora-A is overexpressed in EC tissues, compared with normal endometrium and Aurora-A expression is associated with decreased overall survival. Overexpression of Aurora-A in EC cell lines (Ishikawa and HEC-1B cells) promotes cell proliferation and induced paclitaxel- and cisplatin-resistance. Furthermore, Aurora-A activating AKT-mTOR pathway further induces chemoresistance in vitro, consistent with a positive correlation between Aurora-A and phosphorylated AKT/4E-BP1 expression in EC tissues. In summary, our study provides the strong evidence that Aurora-A controls the sensitivity of EC cell lines to chemotherapy via AKT/mTOR pathway, indicating that pharmacologic intervention of Aurora-A and AKT/mTOR in combination with chemotherapy may be considered for the targeted therapy against EC with overexpression of Aurora-A.

Highlights

Endometrial cancer (EC) is the most common gynecological cancer, and its incidence is increasing [1]
In a complex organism, Aurora-A is an oncogene in mammary epithelium and glands [11, 12], whereas it could be a tumor suppressor in neural stem cells [13], so it should be considered that Aurora-A has cell type-specific functions
Aurora-A is an oncogene in mammary epithelium and gland [11, 12], whereas it functions as a tumor suppressor in neural stem cells [13], so Aurora-A functions differ depending on the cell type

Summary

Introduction

Endometrial cancer (EC) is the most common gynecological cancer, and its incidence is increasing [1]. The molecular mechanisms promoting EC progression need to be further studied and a strategy to overcome and/or prevent chemoresistance is crucial to improve efficacy of EC treatment. Aberrant expression of Aurora-A has been implicated in the initiation, development, and progression of a wide range of malignancies, Aurora-A Activates Akt/mTOR Pathway including colon carcinoma, lymphoma, gastrointestinal adenocarcinomas, breast cancer, and bladder cancer [5,6,7]. As soon as a strong link between Aurora-A and cancer was found, many pharmaceutical companies quickly started trying to develop Aurora-A inhibitors for cancer treatment. Inhibitors of Aurora kinases, such as MLN8237 [8], MK-5108 [9], and ENMD-2076 [10], have been developed but none have yet gone beyond Phase III trials [5], suggesting the functions of Aurora-A have not been fully understood in cancer cells. In a complex organism, Aurora-A is an oncogene in mammary epithelium and glands [11, 12], whereas it could be a tumor suppressor in neural stem cells [13], so it should be considered that Aurora-A has cell type-specific functions

Methods

Results

Conclusion