title: BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer.
abstract: Colon cancer is one of the most common malignancies of the digestive system. Although more effective therapeutic strategies have been developed in the last decades, there is still a great clinical need to explore new treatment regimens for colon cancer due to the undesirable prognosis. In the present study, we investigated the anticancer activity of resveratrol (Res) in human colon cancer cells, and the possible mechanism underlying this effect. We employed crystal violet staining, flow cytometry and western blotting to test the antiproliferation- and apoptosis-inducing effects of Res in LoVo cells. A xenograft tumor model was also introduced to confirm the in vivo anticancer effect of Res. Using PCR, western blotting, a recombinant adenovirus and a specific inhibitor of p38 MAPK or bone morphogenetic protein receptor (BMPR) to explore the possible molecular mechanisms. We found that Res markedly inhibited the proliferation and promoted the apoptosis of LoVo cells, and suppressed the in vivo tumor growth of colon cancer. Res substantially upregulated the expression of bone morphogenetic protein 9 (BMP9). Exogenous expression of BMP9 enhanced the anticancer effect of Res in LoVo cells, while BMP9 knockdown partly reduced this activity. Res increased the activation of p38 MAPK, which was enhanced by the exogenous expression of BMP9. The anticancer activity of Res, or Res combined with BMP9, was reduced partly by the p38 MAPK inhibitor. The BMPR inhibitor almost abolished the Res-induced activation of p38 MAPK, and attenuated the antiproliferative effect of Res in the LoVo cells. Our findings strongly suggest that the anticancer effect of Res in human colon cancer cells may be partly mediated by upregulation of BMP9 to activate p38 MAPK in a BMPR-dependent manner.
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing, 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, P.R. China.
authors.forename: Dong-Xu
authors.initials: DX
authors.lastname: Wang
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing, 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, 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, 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, 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, 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, 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, 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, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing, P.R. China.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing, 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, 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, P.R. China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Sun
authors.affiliation: Chongqing Municipal Key Laboratory of Higher Education Institutions for Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing, P.R. China.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D005434:Flow Cytometry; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D013267:Stilbenes; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol