title: Ovatodiolide Targets β -Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma.
abstract: Dysregulated β -catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potential β -catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β -catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 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 of Anisomeles indica, inhibited β -catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β -catenin (S552) that inhibited β -catenin nuclear translocation. Moreover, ovatodiolide decreased β -catenin stability and impaired the association of β -catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β -catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan ; Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan.
authors.forename: Jar-Yi
authors.initials: JY
authors.lastname: Ho
authors.forename: Ren-Jun
authors.initials: RJ
authors.lastname: Hsu
authors.forename: Chieh-Lin
authors.initials: CL
authors.lastname: Wu
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Chang
authors.forename: Tai-Lung
authors.initials: TL
authors.lastname: Cha
authors.forename: Dah-Shyong
authors.initials: DS
authors.lastname: Yu
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Yu