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

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.

Toad Venom Antiproliferative Activities on Metastatic Melanoma: Bio-Guided Fractionation and Screening of the Compounds of Two Different Venoms

“…In cancer cells, the Na + /K + -ATPase pump also acts as a scaffolding protein when localized in caveolae. In this case, the pump acts as a signal transducer and regulates many processes implicated in tumor development [48][49][50]. The pump is overexpressed in many cancer types, including melanoma [24].…”

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

“…Moreover, bufalin has been shown to inhibit the growth of tumors in a xenograft model of breast cancer [32]. Bufalin has also been reported to inhibit the PI3K-Akt-mTOR pathway which is known to contribute to eIF4F assembly [33].…”

Correlation of p16 and cyclin D1 expression with the incidence and prognosis of cardiac carcinoma

“…It has been proven that smoking, stimulating beverages, irregular diet, gastrointestinal inflammation and gastroesophageal reflux are precipitating factors for cardiac carcinoma. Currently, surgical resection is the most effective treatment means for cardiac carcinoma, but the poor prognosis of patients is still an important reason affecting the therapeutic effect (4,5).…”