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
1
Department of Nursing, Meiho University, Pingtung 91202, Taiwan
2
Department of Food and Nutrition, Meiho University, Pingtung 91202, Taiwan
3
Yu Jun Biotechnology Co., Ltd., Kaoshiung 807, Taiwan
4
Department of Pediatrics, Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan
5
National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Mar. Drugs 2019, 17(12), 668; https://doi.org/10.3390/md17120668
Received: 29 October 2019 / Revised: 21 November 2019 / Accepted: 26 November 2019 / Published: 27 November 2019
(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)
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.
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Keywords:
sinulariolide; soft coral; gastric cancer cells; cell migration; cell invasion
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MDPI and ACS Style
Wu, Y.-J.; Lin, S.-H.; Din, Z.-H.; Su, J.-H.; Liu, C.-I. 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. Mar. Drugs 2019, 17, 668.
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