title: Oridonin inhibits the proliferation of human osteosarcoma cells by suppressing Wnt/β-catenin signaling.
abstract: It has been reported that oridonin (ORI) can inhibit proliferation and induce apoptosis in various types of cancer cell lines. However, the exact mechanism for this function remains unclear. In this study, we investigated the proliferation inhibitory effect of ORI on human osteosarcoma (OS) 143B cells and dissected the possible molecular mechanism(s) underlying this effect. We demonstrated that ORI can inhibit proliferation, induce apoptosis and arrest the cell cycle in 143B cells. Using luciferase reporter assay, we found that the Wnt/β-catenin signaling was inhibited in 143B cells by ORI. Accordingly, the total protein levels and nuclear translocation of β-catenin were reduced by ORI treatment. ORI increased glycogen synthase kinase 3β (GSK3β) activity and upregulated Dickkopf-1 (Dkk-1) expression. We found that Dkk-1 overexpression or β-catenin knockdown can potentiate the proliferation inhibitory effect of ORI in 143B cells, while β-catenin overexpression attenuated this effect. Using the xenograft tumor model of human OS, we demonstrated that ORI effectively inhibited the growth of tumors. Histological examination showed that ORI inhibited cancer cell proliferation, decreased the expression of PNCA and β-catenin. Our findings suggest that ORI can inhibit 143B OS cell proliferation by downregulating Wnt/β-catenin signal transduction, which may be mediated by upregulating the Dkk-1 expression and/or enhancing the function of GSK3β. Therefore, ORI can be potentially used as an effective adjuvant agent for the clinical management of OS.
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Ying-Zi
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Ran-Xi
authors.initials: RX
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Zi-Jun
authors.initials: ZJ
authors.lastname: Meng
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Luo
authors.affiliation: Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: Zuo
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Liang-Jun
authors.initials: LJ
authors.lastname: Yin
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Deng
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, P.R. China.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; C011959:oridonin