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Int. J. Mol. Sci. 2018, 19(5), 1370; https://doi.org/10.3390/ijms19051370

The Effect of Bornyl cis-4-Hydroxycinnamate on Melanoma Cell Apoptosis Is Associated with Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

1
Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91202, Taiwan
2
Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan
3
Department of Biological Science and Technology, Meiho University, Pingtung 91202, Taiwan
4
Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
5
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
*
Author to whom correspondence should be addressed.
Received: 6 April 2018 / Revised: 22 April 2018 / Accepted: 28 April 2018 / Published: 4 May 2018
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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. View Full-Text
Keywords: melanoma; bornyl cis-4-hydroxycinnamate; proteomic; mitochondrial dysfunction; apoptosis; endoplasmic reticulum stress melanoma; bornyl cis-4-hydroxycinnamate; proteomic; mitochondrial dysfunction; apoptosis; endoplasmic reticulum stress
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Yang, T.-Y.; Wu, Y.-J.; Chang, C.-I.; Chiu, C.-C.; Wu, M.-L. The Effect of Bornyl cis-4-Hydroxycinnamate on Melanoma Cell Apoptosis Is Associated with Mitochondrial Dysfunction and Endoplasmic Reticulum Stress. Int. J. Mol. Sci. 2018, 19, 1370.

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