Cardiac glycoside bufalin blocks cancer cell growth by inhibition of Aurora A and Aurora B activation via PI3K-Akt pathway.

Chuan-Ming Xie,Ye Tan,Jun Zhang,Di Wu,Xiao-Tong Lin,Christopher H.K Cheng

doi:10.18632/oncotarget.24475

Abstract

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.

Highlights

The sodium pump is one of the most ubiquitously expressed proteins at the plasma membrane of all mammalian cells, which is known for its critical role in regulating cell volume and membrane potential by transporting 3 Na+ out and 2 K+ into cells utilizing energy from ATP hydrolysis
Our previous studies have demonstrated that sodium pump inhibitors cardiac glycosides can delay mitotic entry and arrest cell cycle in mitosis in a lot of cancer cells via Plk1 pathway [9]
Gurley et al reported that histone Histone H3 (H3) was phosphorylated to stimulate chromosome condensation in mitosis [26], which is consistent with our finding that mitotic cells had high levels of phospho-histone H3

Summary

Introduction

The sodium pump is one of the most ubiquitously expressed proteins at the plasma membrane of all mammalian cells, which is known for its critical role in regulating cell volume and membrane potential by transporting 3 Na+ out and 2 K+ into cells utilizing energy from ATP hydrolysis. Studies have reported that sodium pump functions as a signaling transducer that regulates Src kinase, NF-κB and PI3K [1,2,3]. A functional unit of sodium pump would comprise minimally one α- and one β-subunit [5]. Besides regulating cell volume and membrane potential, the sodium pump www.impactjournals.com/oncotarget has been reported to play a key role in cell growth, differentiation and cell death, but the mechanisms are still not completely understood

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