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.
Oncol Rep. 2016 May;35(5):2691-8. doi: 10.3892/or.2016.4654. Epub 2016 Mar 7.
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.
冬凌草甲素（ORI）是从冬凌草中分离得到的二萜类化合物，已被报道为治疗结肠癌有前途的化疗药物；然而，这种抗癌活性的确切机制仍不清楚。在本研究中，我们研究了 ORI 在 HCT116 细胞中的抗癌作用，并剖析了这种活性的可能分子机制。通过结晶紫染色、流式细胞术和 Western blot 分析，我们发现 ORI 能有效抑制 HCT116 细胞的增殖并诱导其凋亡。进一步的结果分析表明，ORI 能显著上调 HCT116 细胞中的 BMP7，但其在 FHC 细胞中的内源性表达明显低于结肠癌细胞系。BMP7 的外源性表达抑制了 HCT116 细胞的增殖，并显著增强了 ORI 的抗癌作用。然而，BMP7 的特异性抗体几乎消除了 ORI 在 HCT116 细胞中的这种抗癌活性。同时，ORI 对磷酸化 Smad1/5/8 或总 p38 MAPK 的水平没有显著影响，但能显著增加 HCT116 细胞中磷酸化 p38 MAPK 的水平。p38 MAPK 的特异性抑制剂部分逆转了 BMP7 在 HCT116 细胞中的抗增殖作用，但显著促进了 BMP7 抗体对增殖的作用。BMP7 的外源性表达增加了 ORI 诱导的 p38 MAPK 磷酸化，而 BMP7 抗体几乎消除了 ORI 升高的 p38 MAPK 磷酸化。我们的研究结果表明，ORI 可能是治疗结肠癌的有效药物。ORI 的这种抗癌活性可能是通过上调 BMP7 至少增加 p38 MAPK 的激活来介导的。
