Bornyl cis-4-Hydroxycinnamate Suppresses Cell Metastasis of Melanoma through FAK/PI3K/Akt/mTOR and MAPK Signaling Pathways and Inhibition of the Epithelial-to-Mesenchymal Transition

Yang, Tzu-Yen; Wu, Mei‐Li; Chang, Chi-I; Liu, Chih-I; Cheng, Te-Chih; Wu, Yu-Jen

doi:10.3390/ijms19082152

Cited by 19 publications

(22 citation statements)

References 37 publications

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“…It plays an important role in the maintenance of cell tension and signal transduction for cell survival. In recent years, numerous studies have shown that FA-related structural molecules are involved in the regulation of tumor cell epithelial mesenchymal transition (EMT) processes and the promotion of tumor invasion and metastasis ( Akrida et al, 2018 ; Desgrosellier et al, 2014 ; Li et al, 2018a ; Nam et al, 2012 ; Yang et al, 2018a ). Focal adhesion kinases (FAK) can be involved in carcinogenic signaling in the invasion and migration of bladder cancer cells ( Kong, Chen & Sima, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of key candidate genes and biological pathways in bladder cancer

Gào¹,

Chen²,

Chen³

et al. 2018

PeerJ

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BackgroundBladder cancer is a malignant tumor in the urinary system with high mortality and recurrence rates. However, the causes and recurrence mechanism of bladder cancer are not fully understood. In this study, we used integrated bioinformatics to screen for key genes associated with the development of bladder cancer and reveal their potential molecular mechanisms.MethodsThe , , and expression profiles were downloaded from the Gene Expression Omnibus database, and these datasets contain 304 tissue samples, including 81 normal bladder tissue samples and 223 bladder cancer samples. The RobustRankAggreg (RRA) method was utilized to integrate and analyze the four datasets to obtain integrated differentially expressed genes (DEGs), and the gene ontology (GO) functional annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed. Protein-protein interaction (PPI) network and module analyses were performed using Cytoscape software. The OncoLnc online tool was utilized to analyze the relationship between the expression of hub genes and the prognosis of bladder cancer.ResultsIn total, 343 DEGs, including 111 upregulated and 232 downregulated genes, were identified from the four datasets. GO analysis showed that the upregulated genes were mainly involved in mitotic nuclear division, the spindle and protein binding. The downregulated genes were mainly involved in cell adhesion, extracellular exosomes and calcium ion binding. The top five enriched pathways obtained in the KEGG pathway analysis were focal adhesion (FA), PI3K-Akt signaling pathway, proteoglycans in cancer, extracellular matrix (ECM)-receptor interaction and vascular smooth muscle contraction. The top 10 hub genes identified from the PPI network were vascular endothelial growth factor A (VEGFA), TOP2A, CCNB1, Cell division cycle 20 (CDC20), aurora kinase B, ACTA2, Aurora kinase A, UBE2C, CEP55 and CCNB2. Survival analysis revealed that the expression levels of ACTA2, CCNB1, CDC20 and VEGFA were related to the prognosis of patients with bladder cancer. In addition, a KEGG pathway analysis of the top 2 modules identified from the PPI network revealed that Module 1 mainly involved the cell cycle and oocyte meiosis, while the analysis in Module 2 mainly involved the complement and coagulation cascades, vascular smooth muscle contraction and FA.ConclusionsThis study identified key genes and pathways in bladder cancer, which will improve our understanding of the molecular mechanisms underlying the development and progression of bladder cancer. These key genes might be potential therapeutic targets and biomarkers for the treatment of bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of key candidate genes and biological pathways in bladder cancer

Gào¹,

Chen²,

Chen³

et al. 2018

PeerJ

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“…The Transwell assay was performed as described in a previous study [56]. AGS and NCI-N87 cells in serum-free media were placed in an uncoated Boyden chamber (Neuro Probe, Cabin John, MD, USA) at 5 × 10 4 cells/well, and cultured with or without sinulariolide treatment in a 37 • C CO 2 incubator for 24 h to allow cells to migrate through the membrane.…”

Section: Cell Migration and Invasion Analysis By Transwell Assaymentioning

confidence: 99%

“…A gelatin zymography assay was employed to determine the proteolytic activities of MMP-2/-9. The experimental protocol was according to Yang's study [56]. AGS and NCI-N87 cells were treated with sinulariolide at concentrations of 2, 4, 8, and 10 M for 24 h. Samples of conditional media were collected and concentrated using a vacuum concentrator.…”

Section: Gelatin Zymography Assaymentioning

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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“…Recent reports have demonstrated that the activation of the Akt/mTOR pathway induced by the long noncoding RNAs OECC [ 23 ] and MetaLnc9 [ 24 ] and the transmembrane 7 superfamily member 4 [ 25 ] promotes metastatic progression; conversely, the suppression of the Akt/mTOR pathway in the presence of the ferulic acid derivative FXS-3 [ 26 ], cardamonin [ 27 ] and microRNA-520a-3p [ 28 ] inhibits the metastatic potential of lung cancer cells. Accordingly, the association of the Akt/mTOR pathway with metastatic progression has been reported in other cancer types, including colorectal cancer [ 29 – 31 ], hepatocellular carcinoma [ 32 – 34 ], endometrial cancer [ 35 , 36 ], ovarian cancer [ 37 ], gastric cancer [ 38 – 40 ], melanoma [ 41 ], glioma [ 42 , 43 ], pancreatic ductal adenocarcinoma [ 44 ], nasopharyngeal carcinoma [ 45 , 46 ], osteosarcoma [ 47 – 50 ], renal cell carcinoma [ 51 – 53 ] and prostate cancer [ 54 – 56 ]. In breast cancer, synaptopodin-2 [ 57 ] and caveolin-1 [ 58 ] have been shown to modulate Akt/mTOR-regulated metastatic progression.…”

Section: Discussionmentioning

confidence: 99%

The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer

Lin

Kuei

Lee

et al. 2020

Aging

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Lung metastasis (LM) is commonly found in triple-negative breast cancer (TNBC); however, the molecular mechanism underlying TNBC metastasis to lungs remains largely unknown. We thus aimed to uncover a possible mechanism for the LM of TNBC. Here we show that the phosphorylation of Akt and mTORC1 was positively but the autophagy activity was negatively correlated with endogenous Gαh levels and cell invasion ability in TNBC cell lines. Whereas the knockdown of Gαh, as well as blocking its binding with PLC-δ1 by a synthetic peptide inhibitor, in the highly invasive MDA-MB231 cells dramatically suppressed Akt/mTORC1 phosphorylation and blocked autophagosome degradation, the overexpression of Gαh in the poorly invasive HCC1806 cells enhanced Akt/mTORC1 phosphorylation but promoted autophagosome degradation. The pharmaceutical inhibition of autophagy initiation by 3-methyladenine was found to rescue the cell invasion ability and LM potential of Gαh-silenced MDA-MB231 cells. In contrast, the inhibition of mTORC1 activity by rapamycin suppressed autophagosome degradation but mitigated the cell invasion ability and LM potential of Gαh-overexpressing HCC1806 cells. These findings demonstrate that the induction of autophagy activity or the inhibition of Akt-mTORC1 axis provides a useful strategy to combat the Gαh/PLC-δ1-driven LM of TNBC.

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Bornyl cis-4-Hydroxycinnamate Suppresses Cell Metastasis of Melanoma through FAK/PI3K/Akt/mTOR and MAPK Signaling Pathways and Inhibition of the Epithelial-to-Mesenchymal Transition

Cited by 19 publications

References 37 publications

Identification of key candidate genes and biological pathways in bladder cancer

Identification of key candidate genes and biological pathways in bladder cancer

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

The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer

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