Simvastatin Inhibits the Malignant Behaviors of Gastric Cancer Cells by Simultaneously Suppressing YAP and β-Catenin Signaling

Qing Liu,1,2,* Hongwei Xia,2,* Sheng Zhou,1,2 Qiulin Tang,1,2 Jitao Zhou,1 Min Ren,1 Feng Bi1,2 1Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng BiDepartment of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of ChinaTel +86 189 8060 1771Email bifeng@scu.edu.cnBackground: Statins, which are used to lower blood cholesterol levels by inhibiting HMG-CoA reductase, have shown anticancer effects in many cancer cells. However, the role of statins in gastric cancer remains unclear. This study aims to investigate whether the statins could antagonize progression of gastric cancer cells and tried to find the molecule mechanism.Methods: Effects of simvastatin on the morphology, proliferation, migration, apoptosis, and invasion of gastric cancer cells were detected and compared. Western blotting, cell viability assay, fluorescence, and transfection were employed to study the molecule mechanism of the effects and the interaction between YAP and β-catenin signaling.Results: Simvastatin could inhibit proliferation, migration and invasion, and promote the apoptosis in gastric cancer cells. Mechanistic studies showed that simvastatin treatment could inhibit the expression of β-catenin and the activity of YAP and the downstream targets of YAP and β-catenin in gastric cancer cells. Moreover, we found that YAP and β-catenin could form a positive feedback loop in gastric cancer cells. Further investigation revealed that simvastatin mainly acted through by inhibiting the activity of RhoA to inhibit YAP and β-catenin, and the geranylgeranyl pyrophosphate pathway mediated this regulation.Conclusion: Statins represent a promising therapeutic option for gastric cancer by simultaneously targeting YAP and β-catenin signaling.Keywords: gastric cancer, simvastatin, YAP, β-catenin, RhoA