Ovatodiolide Targetsβ-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

Abstract

Dysregulatedβ-catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potentialβ-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening forβ-catenin signaling inhibitors involvedin silicoinquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell linesin vitroand 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound ofAnisomeles indica, inhibitedβ-catenin signaling and reduced RCC cell viability, survival, migration/invasion, andin vitrocell orin vivomouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylatedβ-catenin (S552) that inhibitedβ-catenin nuclear translocation. Moreover, ovatodiolide decreasedβ-catenin stability and impaired the association ofβ-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potentβ-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.