Bufalin and Atezolizumab Combination Suppresses Bladder Cancer via Negative Regulatory Activity on YAP/TEAD1 Signaling

Abstract

Background: Bladder cancer is a genitourinary tumor which threatens the health of a large segment of the population. Surgical treatment and chemotherapy have severe side effects and a high risk of recurrence. Thus, effective adjuvant drugs are urgently needed. Herein, we set out to examine whether bufalin might improve the therapeutic effect of atezolizumab on bladder cancer cells. Methods: 5-ethynyl-2-deoxyuridine (EdU) and methyl tetrazolium (MTT) methods were used to examine cell proliferation, while flow cytometry and Transferase-Mediated dUTP Nick-End Labeling (TUNEL) staining were used to test cell apoptosis. A tumor xenograft model in nude mice was also applied. Western blot detection of the phosphorylated-Yes-associated protein (p-YAP), Cyclin E, TEA domain transcription factor 1 (TEAD1), Mammalian sterile 20-like kinase 1 (MST1) and p-LASTS1 protein expression was performed. Results: Both bufalin and atezolizumab suppressed bladder tumor cell proliferation, migration and invasion. They also reduced Yes-associated protein (YAP)/TEAD1 signaling which was counteracted by YAP overexpression. In addition, bufalin or atezolizumab alone inhibited the activity of tumor growth in vivo, blocked the growth of cells in the G1 phase and triggered apoptosis. Furthermore, combined bufalin and atezolizumab showed additional inhibitory activity in the above experiments, indicating an improved therapeutic effect. Conclusions: Atezolizumab combined with bufalin may be an effective therapeutic approach for bladder cancer. The mechanism of action of the combined treatment may be correlated with activating the MST1/LASTS1 pathway and inhibiting the YAP/TEAD1 signaling pathway.