Sinulariolide Suppresses Human Hepatocellular Carcinoma Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 through MAPKs and PI3K/Akt Signaling Pathways

Wu, Yu-Jen; Neoh, Choo-Aun; Tsao, Chia-Yu; Su, Jui‐Hsin; Li, Hsing-Hui

doi:10.3390/ijms160716469

Cited by 78 publications

(54 citation statements)

References 45 publications

(47 reference statements)

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“…This phenomenon may be regulated by the activation of the PI3K/Akt and MAPK signaling pathways (17). The data of the present study indicated that the PI3K/Akt cascade may directly or indirectly regulate the properties of migration and invasion in sorafenib-resistant cells via MMP-2 and MMP-9.…”

Section: Discussionmentioning

confidence: 48%

Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

Zhang

Wang

et al. 2018

Oncol Lett

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Abstract. Long-term sorafenib treatment triggers resistance to chemotherapy in patients with hepatocellular carcinoma (HCC). In order to investigate the mechanisms of sorafenib resistance in HCC, the aim of the present study was to develop a resistant human liver cell line via long-term exposure to sorafenib. The cytotoxicity cell counting kit-8 assay was used to evaluate drug sensitivity. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to examine the molecular mechanisms underpinning sorafenib resistance. Migratory and invasive properties in resistant cells were assessed using Transwell assays. The results from the present study revealed that resistant cells became insensitive to sorafenib treatment and exhibited increased migratory and invasive capacities. Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway and epithelial-mesenchymal transition was characteristic of resistant cells. The use of LY294002, a PI3K inhibitor, was able to suppress the activation of Akt and extracellular signal-regulated kinase 1/2, attenuated the migratory and invasive capacities of resistant cells. Data from the present study indicates that inhibition of the PI3K signaling pathway with LY294002 exerts suppressive effects on sorafenib resistance and provides an attractive novel therapeutic regime in patients with advanced HCC.

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Section: Discussionmentioning

confidence: 48%

Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

Zhang

Wang

et al. 2018

Oncol Lett

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“…[24][25][26] Besides, several very recent studies have showed that the PI3K/Akt pathway negatively regulated MMP-2 secretion in several types of cells, including vascular smooth muscle cells, hepatocellular carcinoma cells, and glioblastoma cells. [27][28][29] The activation of the PI3K/Akt pathway caused upregulation of Forkhead Box O3 (FoxO3a), a famous tumor suppressor, and suppressed MMP-2 expression to inhibit the migration vascular smooth muscle cells. 27 Moreover, in cardiovascular epithelial cells, FoxO3a was also reported to have a protective effect through suppressing secretion of ET-1 and proinflammatory factors.…”

Section: Discussionmentioning

confidence: 99%

CTRP9 Ameliorates Pulmonary Arterial Hypertension Through Attenuating Inflammation and Improving Endothelial Cell Survival and Function

Xu²,

Wang³

et al. 2016

Journal of Cardiovascular Pharmacology

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Endothelial dysfunction and inflammation are believed to be 2 primary instigators of pulmonary arterial hypertension (PH). C1q/TNF-related protein 9 (CTRP9) plays important roles in anti-inflammation and improvement of epithelial function. However, the role of CTRP9 in the progression of PH remains still unclear. In this study, the role and mechanism of CTRP9 in the PH progression were explored. First, serum CTRP9 contents and CTRP9 mRNA expression in the pulmonary artery epithelial cells from patients with PH were detected. Our data on enzyme-linked immunosorbent assay and real-time quantitative Polymerase Chain Reaction showed that CTRP9 mRNA and protein content were markedly downregulated in the patients with PH. Then the pcDNA-CTRP9 expression vector or CTRP9 siRNA was transfected into the primary pulmonary artery epithelial cells from the patients with PH in vitro. CTRP9 overexpression significantly improved endothelial NOS protein expression and reduced the secretion of endothelin-1 (ET-1) and matrix metalloproteinase-2 (MMP-2), whereas knockdown of CTRP9 sharply reduced eNOS protein expression and promoted the secretion of ET-1 and MMP-2 in the cultured human epithelial cells. Moreover, the levels of phosphatidylinositol 3-kinase (PI3K) and pAkt were reduced in the epithelial cells and CTRP9 overexpression activated the PI3K/Akt pathway. CTRP9 could inhibit cell apoptosis and eNOS expression reduction in the cells pretreated with the PI3K/Akt inhibitor LY294002 and resist LY294002-induced ET-1 and MMP-2 secretion. Finally, to verify the role of CTRP9 in the progression of PH in vivo, the pcDNA-CTRP9 expression vector or CTRP9 siRNA was intravenously injected into rats with PH. Pulmonary arterial pressures of the rats were notably reduced by the pcDNA-CTRP9 injection and elevated by the CTRP9 siRNA injection. In conclusion, CTRP9 ameliorated PH by attenuating inflammation and improving endothelial cell survival and function.

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“…Furthermore, cytotoxicity is one of the main characteristics of such compounds [9][10][11]. Many researchers have reported that compounds isolated from marine soft corals, such as diterpenoids, diterpenes, and prostanoids, have an effect on apoptosis in several types of cancer cells, including melanoma, oral squamous cell carcinoma, bladder, breast, cervical, colon, and liver cancer cells [12][13][14][15][16][17][18]. Sinulariolide is an active compound extracted from cultured soft coral Sinularia flexibilis.…”

Section: Introductionmentioning

confidence: 99%

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

Lin²,

Din

et al. 2019

Marine Drugs

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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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Sinulariolide Suppresses Human Hepatocellular Carcinoma Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 through MAPKs and PI3K/Akt Signaling Pathways

Cited by 78 publications

References 45 publications

Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

CTRP9 Ameliorates Pulmonary Arterial Hypertension Through Attenuating Inflammation and Improving Endothelial Cell Survival and Function

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

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