BMP 9 / p 38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer

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 antiproliferationand 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. Introduction Colon cancer is one of the most common malignancies in the digestive system. Current treatments include surgical resection, radiotherapy, chemotherapy and targeted therapy alone or in combination. However, the prognosis remains unsatisfactory (1,2). Thus, there is a great clinical need to explore new agents for the treatment of colon cancer. Numerous herbs or their components have been clinically used as potential candidates for anticancer agents, such as camptothecin, vincristine and taxol (3-5). Polyphenolic compounds are highly present in red wine, and some reports and clinical epidemiologic studies have demonstrated that red wine contributes to a reduction in cardiovascular diseases and cancer risk (6,7). Resveratrol (3,5,4'-trihydroxystilbene, Res), a polyphenolic compound from beans and grapes, was discovered in red wine by Siemann and Creasy in 1992, and can be used as a platelet aggregation inhibitor, cardiac-protection and anticancer agent (8,9). It has been reported that Res can inhibit the proliferation and promote the apoptosis of various types of cancer cells, such as colon, breast and prostate (10-12). For colon cancer, although the anticancer effects of Res have been validated (10), the precise mechanisms underlying these activities remain unclear. Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) superfamily (13). Approximately 20 BMPs have been identified to date, and they exert multifunctions to regulate physiological processes, such as proliferation, differentiation, adhesion, migration and apoptosis (14,15). Thus, the aberrant expression of BMPs and/or downstream signal cascades have been implicated in the pathogenesis of various types of cancer, such as colon cancer (16,17). Therefore, BMPs and/or the downstream signal cascades may be used as potential targets for colon cancer treatment (15,18). BMP9 is the most potent BMP member to induce osteogenic differentiation in mesenchymal stem cells to date (19). Apart from promoting osteogenic differentiation, BMP9 is also implicated in cancer, although the outcome is controversial. BMP9 inhibits the proliferation of breast and prostate cancer cells (20,21), but promotes the proliferation of osteosarcoma, ovarian and liver cancer cells (22-24). The BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer SHUANG-XUE YUAN1,2, DONG-XU WANG1,2, QIU-XIANG WU1,2, Chun-MEI REn1,2, YANG LI1,2, QIAN-ZHAO CHEN1,2, YU-HUA ZENG1,2, YING SHAO1,2, JUN-QIN YANG1,2, YAN BAI1,2, PU ZHANG1,2, YU YU1,3, KE Wu1,2, WEN-JUAN SUN1,2 and BAI-CHENG HE1,2 1Chongqing Municipal Key Laboratory of higher Education Institutions for Biochemistry and Molecular Pharmacology; Departments of 2Pharmacology and 3Chemistry, School of Pharmacy, Chongqing Medical university, Yuzhong, Chongqing, P.R. China Received August 13, 2015; Accepted October 12, 2015 DOI: 10.3892/or.2015. 4407 Correspondence to: Professor Bai-Cheng He, Department of Pharmacology, School of Pharmacy, Chongqing Medical university, 1 Yixueyuan Road, Yuzhong, Chongqing 400016, P.R. China E-mail: 894704897@qq.com; hebaicheng99@yahoo.com