Cardiac glycoside bufalin blocks cancer cell growth by inhibition of Aurora A and Aurora B activation via PI3K-Akt pathway
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Chuan-Ming Xie1, Xiao-Tong Lin1,*, Di Wu1,*, Ye Tan1, Christopher H.K. Cheng2,3 and Jun Zhang4
1Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
2School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
3Center of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
4Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
*These authors contributed equally to this work
Keywords: bufalin; Aurora kinase; PI3K/Akt; cancer; mitosis
Received: September 13, 2017 Accepted: January 30, 2018 Published: February 09, 2018
In our previous study, cardiac glycosides including bufalin, a group of sodium pump (Na+/K+-ATPase) inhibitors widely used to treat heart failure for many years, have been demonstrated to induce a delay of mitotic entry and mitotic arrest in many cancer cells. However, the underlying mechanism remains poorly understood. Here, we reported for the first time that cardiac glycoside bufalin induced mitotic entry delay and prometaphase arrest by inhibition of activation of Aurora A/B. Furthermore, cardiac glycoside bufalin prevented Aurora A recruitment to mitotic centrosomes and Aurora B recruitment to unattached kinetochores. Mechanistically, bufalin and knockdown of sodium pump inhibited PI3K-Akt pathway, which in turn inhibit the activation of Aurora A/B, followed by a delay in mitotic entry and mitotic arrest. These actions were reversed by overexpression of Akt. In addition, ERK, mTOR, and ROS are not involved in bufalin-mediated downregulation of active form of Aurora A/B. Taken together, cardiac glycoside bufalin induces mitotic entry delay and mitotic arrest in cancer cells through inhibition of Aurora A/B activation via PI3K-Akt pathway. Based on this novel finding we could suggest that targeting PI3K-Akt pathway may have therapeutic value for the treatment of cancers associated with sodium pump overexpression.
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