Department of Nursing, Meiho University, Pingtung 91202, Taiwan.
Department of Food and Nutrition, Meiho University, Pingtung 91202, Taiwan.
Mar Drugs. 2019 Nov 27;17(12):668. doi: 10.3390/md17120668.
Cancer metastasis is the main cause of death in cancer patients; however, there is currently no effective method to predict and prevent metastasis of gastric cancer. Therefore, gaining an understanding of the molecular mechanism of tumor metastasis is important for the development of new drugs and improving the survival rate of patients who suffer from gastric cancer. Sinulariolide is an active compound isolated from the cultured soft coral . We employed sinulariolide and gastric cancer cells in experiments such as MTT, cell migration assays, cell invasion assays, and Western blotting analysis. Analysis of cell migration and invasion capabilities showed that the inhibition effects on cell metastasis and invasion increased with sinulariolide concentration in AGS and NCI-N87 cells. Immunostaining analysis showed that sinulariolide significantly reduced the protein expressions of MMP-2, MMP-9, and uPA, but the expressions of TIMP-1 and TIMP-2 were increased, while FAK, phosphorylated PI3K, phosphorylated AKT, phosphorylated mTOR, phosphorylated JNK, phosphorylated p38MAPK, and phosphorylated ERK decreased in expression with increasing sinulariolide concentration. From the results, we inferred that sinulariolide treatment in AGS and NCI-N87 cells reduced the activities of MMP-2 and MMP-9 via the FAK/PI3K/AKT/mTOR and MAPKs signaling pathways, further inhibiting the invasion and migration of these cells. Moreover, sinulariolide altered the protein expressions of E-cadherin and N-cadherin in the cytosol and Snail in the nuclei of AGS and NCI-N87 cells, which indicated that sinulariolide can avert the EMT process. These findings suggested that sinulariolide is a potential chemotherapeutic agent for development as a new drug for the treatment of gastric cancer.
癌症转移是癌症患者死亡的主要原因；然而，目前尚无有效的方法来预测和预防胃癌的转移。因此，了解肿瘤转移的分子机制对于开发新的药物和提高胃癌患者的生存率非常重要。辛拉醇是从培养的软珊瑚中分离得到的一种活性化合物。我们采用辛拉醇和胃癌细胞进行实验，如 MTT、细胞迁移实验、细胞侵袭实验和 Western blot 分析。细胞迁移和侵袭能力分析表明，AGS 和 NCI-N87 细胞中，辛拉醇的浓度越高，对细胞转移和侵袭的抑制作用越强。免疫染色分析表明，辛拉醇显著降低了 MMP-2、MMP-9 和 uPA 的蛋白表达水平，而 TIMP-1 和 TIMP-2 的表达水平增加，同时随着辛拉醇浓度的增加，FAK、磷酸化 PI3K、磷酸化 AKT、磷酸化 mTOR、磷酸化 JNK、磷酸化 p38MAPK 和磷酸化 ERK 的表达水平降低。由此推断，辛拉醇处理 AGS 和 NCI-N87 细胞可通过 FAK/PI3K/AKT/mTOR 和 MAPKs 信号通路降低 MMP-2 和 MMP-9 的活性，从而进一步抑制这些细胞的侵袭和迁移。此外，辛拉醇改变了 AGS 和 NCI-N87 细胞细胞质中 E-钙粘蛋白和 N-钙粘蛋白以及核中转录因子 Snail 的蛋白表达水平，表明辛拉醇可以阻止 EMT 过程。这些发现表明辛拉醇可能是一种有前途的化疗药物，可作为治疗胃癌的新药进行开发。
