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.

GPER1 Silencing Suppresses the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Inhibiting PI3K/AKT–Mediated EMT

“…During EMT, cell morphology, cell-cell adhesion, and many cellular pathways are altered, leading to invasion of cancer cells into the surrounding tissue and eventually to tumor metastasis (Lamouille et al, 2013). The phosphoinositol-3-kinase (PI3K) pathway plays an important role in cell proliferation, migration, and invasion, mediates EMT processes (Wu et al, 2019), and is emerging as a promising target in cancer therapy (Barrett et al, 2012;Sharma et al, 2017;Narayanankutty, 2019). G protein-coupled receptors can directly activate most class I PI3k subunits through interaction with Gβγ protein subunits (Pal and Mandal, 2012).…”

Paeonol Suppresses Proliferation and Motility of Non-Small-Cell Lung Cancer Cells by Disrupting STAT3/NF-κB Signaling

“…A growing number of studies have indicated that EMT and MMP enzymes are critically involved in the enhanced motility and invasion of tumor cells ( Wu et al, 2019 ). The event of EMT characterized by loss of E-cadherin and upregulation of N-cadherin can promote the transformation of tumor cell phenotype, rending the acquisition of fibroblast-like characteristics and leading to decreased cell adhesion and increased motility ( Li et al, 2019 ).…”

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…Additional studies suggest that HIV protease inhibitors could impair MMP-9 activity also because of their ability to upregulate TIMPs levels [ 171 , 197 ], diminish the production of nitric oxide and reduce the expression of MT1-MMP [ 192 , 198 , 199 , 200 , 201 ]. The fact that they reduce the expression of MMPs while increasing that of TIMPs makes HIV-protease inhibitors similar to natural compounds that perform these actions thanks to the same ability to hamper the AKT and MAPK signaling pathways [ 202 , 203 ]. Also, synthetic antagonists of α1-antitrypsin, an endogenous protease inhibitor which is overexpressed in tumor tissues, downregulate MMPs and, at the same time, upregulate TIMPs via PI3K/AKT inhibition [ 204 ].…”