Sinulariolide Inhibits Gastric Cancer Cell Migration and Invasion through Downregulation of the EMT Process and Suppression of FAK/PI3K/AKT/mTOR and MAPKs Signaling Pathways.

Abstract

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 Sinularia flexibilis. 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.

• Authors: Yu-Jen Wu, Shih-Hsiung Lin, Zhong-Hao Din, Jui-Hsin Su, Chih-I Liu
• Journal: Marine drugs (Mar Drugs) Vol. 17 Issue 12 (Nov 27 2019) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 31783709 (Publication Type: Journal Article)

Chemical References

• Diterpenes
• TIMP2 protein, human
• Tissue Inhibitor of Metalloproteinase-2
• sinulariolide
• MTOR protein, human
• Focal Adhesion Kinase 1
• PTK2 protein, human
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Cell Movement (drug effects)
• Diterpenes (pharmacology)
• Down-Regulation (drug effects)
• Focal Adhesion Kinase 1 (metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• Neoplasm Metastasis (drug therapy)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy)
• TOR Serine-Threonine Kinases (metabolism)
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)