Drug Design, Development and Therapy (Mar 2022)
Clotrimazole Inhibits HCC Migration and Invasion by Modulating the ERK-p65 Signaling Pathway
Abstract
Xudong Liu,1– 3 Jie Gao,1– 3 Yaohui Sun,1– 3 Feng Zhang,1– 3 Wenzhi Guo,1– 3 Shuijun Zhang1– 3 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Henan Research & Development International Joint Laboratory for Organ Transplantation Immunomodulation, Zhengzhou, Henan Province, People’s Republic of China; 3National Regional Medical Treatment Centre of Henan Organ Transplantation, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Shuijun Zhang, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan Province, People’s Republic of China, Tel/Fax +8637166913032, Email [email protected]: Hepatocellular carcinoma (HCC), has a very high mortality rate and is the most common type of liver cancer. Clotrimazole, a traditional antifungal drug, has garnered considerable attention as a therapeutic strategy for HCC. However, its effects against the migration and invasion of HCC cells as well as the associated underlying mechanisms remain unclear. Therefore, in this study, we investigated its effects on HCC and attempted to elucidate the underlying molecular mechanisms.Methods: CCK-8 was used to investigate the inhibitory effect of clotrimazole on the proliferation of different types of HCC cells, and wound healing and transwell assays were performed to investigate its inhibitory effect on the invasion and migration of the HCC cells. Further, western blotting was employed to detect changes in the expression levels of epithelial mesenchymal transition (EMT)-related proteins, extracellular-regulated protein kinases (ERK), p-ERK, p65, and p-p65. We also used ERK activators in combination with clotrimazole to treat the HCC cell lines.Results: Clotrimazole inhibited the invasion and migration of HCC cells, and mechanistically, it exerted these anti-tumor effects via EMT by repressing ERK phosphorylation.Conclusion: These findings suggest that clotrimazole inhibits HCC metastasis by repressing EMT in an ERK dephosphorylation-dependent manner.Keywords: hepatocellular carcinoma, clotrimazole, extracellular-regulated protein kinases, migration, invasion, cancer
