Niclosamide suppresses renal cell carcinoma by inhibiting Wnt/?-catenin and inducing mitochondrial dysfunctions.

ABSTRACT: To investigate the effects of anthelminthic drug niclosamide in renal cell carcinoma (RCC) and the underlying mechanisms of its action.The effects of niclosamide on the proliferation and apoptosis of RCC cells were examined in vitro and in vivo by using MTS, colony formation assay, flow cytometry and xenograft cancer mouse model. Mechanism studies were performed by analyzing Wnt/?-catenin signaling and mitochondrial functions in a panel of RCC cell lines.We show that niclosamide effectively targets two RCC cell lines through inhibiting proliferation and anchorage-independent colony formation, and inducing apoptosis. It also enhances the inhibitory effects of chemotherapeutic drug cisplatin in two independent in vivo RCC xenograft mouse models. Mechanistically, niclosamide decreases ?-catenin levels and therefore suppresses Wnt/?-catenin activities. Overexpression of ?-catenin partially reverses the inhibitory effects of niclosamide in RCC cells, demonstrating that besides ?-catenin, other mechanisms are involved in niclosamide's anti-cancer activity. Indeed, we further show that niclosamide induces mitochondrial dysfunctions as shown by the decreased level of mitochondrial membrane potential and respiration, resulting in decreased ATP levels and increased reactive oxygen species (ROS) levels.Our findings support the inhibitory effects of niclosamide in cancer and provide better understanding on its underlying mechanism. Our data suggests that niclosamide is a useful addition to the treatment armamentarium for RCC.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC5005241 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature