title: Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK.
abstract: Oridonin (ORI), a diterpenoid purified from Rabdosia rubescens, has been reported as a promising chemotherapy drug for colon cancer treatment; yet, the precise mechanisms underlying this anticancer activity remain unclear. In the present study, we investigated the anticancer effect of ORI in HCT116 cells, and dissected the possible molecular mechanisms underlying this activity. With crystal violet staining, flow cytometry and western blot assay, we found that ORI effectively inhibited the proliferation and induced the apoptosis of HCT116 cells. Further analysis of the results indicated that BMP7 was greatly upregulated by ORI in the HCT116 cells, but its endogenous expression in FHC cells was apparently lower than that in the colon cancer cell lines. Exogenous expression of BMP7 inhibited the proliferation of the HCT116 cells, and substantially potentiated the anticancer effect of ORI. However, the specific antibody of BMP7 nearly abolished this anticancer activity of ORI in the HCT116 cells. Meanwhile, ORI exerted no significant effect on the level of phosphorylated Smad1/5/8 or total p38 MAPK, but greatly increased the level of phosphorylated p38 MAPK in the HCT116 cells. A p38 MAPK-specific inhibitor partly reversed the antiproliferative effect of BMP7 in the HCT116 cells, but prominently promoted the effect of the BMP7 antibody on proliferation. Exogenous expression of BMP7 increased the ORI-induced phosphorylation of p38 MAPK, while the BMP7 antibody almost abolished the ORI-elevated p38 MAPK phosphorylation. Our findings suggest that ORI may be an efficacious drug for colon cancer treatment. This anticancer activity of ORI may be mediated by upregulating BMP7 at least to increase the activation of p38 MAPK.
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Ren
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Qian-Zhao
authors.initials: QZ
authors.lastname: Chen
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Zeng
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Qiu-Xiang
authors.initials: QX
authors.lastname: Wu
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Shuang-Xue
authors.initials: SX
authors.lastname: Yuan
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Jun-Qin
authors.initials: JQ
authors.lastname: Yang
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Sun
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D045786:Diterpenes, Kaurane; C011959:oridonin; D048051:p38 Mitogen-Activated Protein Kinases