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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.

ABSTRACT: Bornyl cis-4-hydroxycinnamate, a bioactive compound isolated from Piper betle stems, has the potential for use as an anti-cancer agent. This study investigated the effects of bornyl cis-4-hydroxycinnamate on cell migration and invasion in melanoma cells. Cell migration and invasion were compared in A2058 and A375 melanoma cell lines treated with/without bornyl cis-4-hydroxycinnamate (1?6 µM). To examine whether bornyl cis-4-hydroxycinnamate has a potential anti-metastatic effect on melanoma cells, cell migration and invasion assays were performed using a Boyden chamber assay and a transwell chamber in A2058 and A375 cells. Gelatin zymography was employed to determine the enzyme activities of MMP-2 and MMP-9. Cell lysates were collected for Western blotting analysis of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase-1/2 (TIMP-1/2), as well as key molecules in the mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK)/ phosphatidylinositide-3 kinases (PI3K)/Akt/ mammalian target of rapamycin (mTOR), growth factor receptor-bound protein 2 (GRB2) signaling pathways. Our results demonstrated that bornyl cis-4-hydroxycinnamate is a potentially useful agent that inhibits melanoma cell migration and invasion, and altered melanoma cell metastasis by reducing MMP-2 and MMP-9 expression through inhibition of the FAK/PI3K/Akt/mTOR, MAPK, and GRB2 signaling pathways. Moreover, bornyl cis-4-hydroxycinnamate inhibited the process of the epithelial-to-mesenchymal transition in A2058 and A375 melanoma cells. These findings suggested that bornyl cis-4-hydroxycinnamate has potential as a chemotherapeutic agent, and warrants further investigation for its use in the management of human melanoma.

SUBMITTER: Yang TY

PROVIDER: S-EPMC6121392 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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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.

Yang Tzu-Yen TY Wu Mei-Li ML Chang Chi-I CI Liu Chih-I CI Cheng Te-Chih TC Wu Yu-Jen YJ

International journal of molecular sciences 20180724 8

Bornyl cis-4-hydroxycinnamate, a bioactive compound isolated from Piper betle stems, has the potential for use as an anti-cancer agent. This study investigated the effects of bornyl cis-4-hydroxycinnamate on cell migration and invasion in melanoma cells. Cell migration and invasion were compared in A2058 and A375 melanoma cell lines treated with/without bornyl cis-4-hydroxycinnamate (1⁻6 µM). To examine whether bornyl cis-4-hydroxycinnamate has a potential anti ...[more]

PMID: 30042328

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Project description:Bornyl cis-4-hydroxycinnamate, an active compound isolated from Piper betle stems, was investigated in terms of its effects on A2058 and A375 melanoma cell proliferation and protein expression in this study. We used flow cytometric analysis to examine the early stages of apoptosis induced by bornyl cis-4-hydroxycinnamate in the two melanoma cell lines and employed comparative proteomic analysis to investigate the effects of this compound on protein expression in A375 cells. Master maps generated by PDQuest software from two-dimensional electrophoresis (2-DE) analysis of A375 cells showed that the expression levels of 35 proteins were significantly altered, with 18 proteins upregulated and 17 downregulated. The proteomics study identified several proteins that are involved in mitochondrial dysfunction and endoplasmic reticulum stress (ER stress), in addition to apoptosis-associated proteins, including prohibitin, hypoxia-upregulated protein 1, stress 70 protein, 78 kDa glucose-regulated protein (GRP78), and protein deglycase DJ-1 (protein DJ-1) in melanoma cells exposed to bornyl cis-4-hydroxycinnamate. The treatment also resulted in a marked decline of the mitochondrial membrane potential, in cytochrome C release into the cytosol, in the activation of Bcl-2-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad), caspase-3, and caspase-9, and in the decreased expression of p-Bad, B-cell lymphoma 2 (Bcl-2), Bcl-xl, and induced myeloid leukemia cell differentiation protein-1 (Mcl-1), indicating that apoptosis induced by bornyl cis-4-hydroxycinnamate was mediated by the mitochondria through the caspase-dependent pathway. Also, salubrinal (an eukaryotic initiation factor 2α inhibitor; eIF2α inhibitor) was able to protect the cells from bornyl cis-4-hydroxycinnamate-induced apoptosis. Bornyl cis-4-hydroxycinnamate-related cell death also implied that the protein kinase R-like endoplasmic reticulum kinase (PERK)?eIF2α?ATF4?CHOP signal pathways was activated upon bornyl cis-4-hydroxycinnamate treatment. Altogether, our results support the conclusion that bornyl cis-4-hydroxycinnamate-induced apoptosis in melanoma cells is associated with mechanisms correlated with the activation of caspase cascades, mitochondrial dysfunction, and endoplasmic reticulum stress, and indicate that this molecule has the potential to be developed as a chemotherapeutic agent for human melanoma.

Project description:Background:Doxorubicin (DOX) is one of the most effective anti-neoplastic drugs although its clinical use is limited by the severe cardiotoxicity. Apoptosis and defective autophagy are believed to contribute to DOX-induced cardiotoxicity. Here we explored the effect of curcumin (Cur) on DOX-induced cardiac injury and the mechanism involved with a focus on oxidative stress, autophagy and pyroptosis. Methods:Kunming mice were challenged with DOX (3 mg·kg-1, i.p. every other day) with cohorts of mice receiving Cur at 50, 100, 200 and 400 mg·kg-1 via gavage daily. Serum levels of cardiac enzymes, such as aspartate amino transferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and heart homogenate oxidative stress markers, such as superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Echocardiographic and cardiac contraction were examined. Apoptosis, pyroptosis, autophagy and Akt/mTOR-signalling proteins were detected using western blot or electron microscopy. Cardiac contractile properties were assessed including peak shortening, maximal velocity of shortening/relengthening (± dL/dt), time-to-PS, and time-to-90% relengthening (TR90). Superoxide levels were evaluated using DHE staining. GFP-LC3 was conducted to measure autophagosomes. Results:Our study showed that Cur protected against cardiotoxicity manifested by a significant decrease in serum myocardial enzymes and improvement of anti-oxidative capacity. Cur inhibited autophagy and offered overt benefit for cardiomyocyte survive against DOX-induced toxicity. Cur attenuated DOX-induced cardiomyocyte pyroptosis as evidenced by NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and interleukin-18 levels. DOX impaired cardiac function (reduced fractional shortening, ejection fraction, increased plasma cTnI level and TR90, decreased PS and ± dL/dt), the effects of which were overtly reconciled by 100 mg·kg-1 but not 50 mg·kg-1 Cur. H9c2 cells exposure to DOX displayed increased intracellular reactive oxygen species (ROS) and autophagy, the effects of which were nullified by Cur. Autophagy activator rapamycin cancelled off Cur-induced protective effects. Conclusions:Our finding suggested that Cur rescued against DOX-induced cardiac injury probably through regulation of autophagy and pyroptosis in a mTOR-dependent manner.

Dataset Information

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.

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

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