Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway |
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Authors: | Su Yu-Ting Chang Huei-Ling Shyue Song-Kun Hsu Shih-Lan |
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Affiliation: | a Institute of Medical Science, China Medical University, Taichung, Taiwan, ROC b School of Medicine, China Medical University, Taichung, Taiwan, ROC c Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC d Department of Education and Research, Taichung Veterans General Hospital No. 160, Section 3, Chung-Gang Road, Taichung, Taiwan, ROC e Institute of Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC f Institute of Chinese Pharmaceutical Sciences, China Medical University, Taichung, Taiwan, ROC |
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Abstract: | Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been reported to exhibit anti-cancer effect on several human cancers such as liver cancers and lung cancers. However, the molecular mechanisms of emodin-mediated tumor regression have not been fully defined. In this study, we show that treatment with 50 μM emodin resulted in a pronounced release of cytochrome c, activation of caspase-2, -3, and -9, and apoptosis in human lung adenocarcinoma A549 cells. These events were accompanied by the inactivation of ERK and AKT, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (Δψm), decrease of mitochondrial Bcl-2, and increase of mitochondrial Bax content. Ectopic expression of Bcl-2, or treatment with aurintricarboxylic acid, furosemide or caspase inhibitors markedly blocked emodin-induced apoptosis. Conversely, pharmacologic ERK and AKT inhibition promoted emodin-induced apoptosis. Furthermore, the free radical scavenger ascorbic acid and N-acetylcysteine attenuated emodin-mediated ROS production, ERK and AKT inactivation, mitochondrial dysfunction, Bcl-2/Bax modulation, and apoptosis. Take together, these findings suggest that in A549 cells, emodin-mediated oxidative injury acts as an early and upstream change in the cell death cascade to antagonize cytoprotective ERK and AKT signaling, triggers mitochondrial dysfunction, Bcl-2 and Bax modulation, mitochondrial cytochrome c release, caspase activation, and consequent leading to apoptosis. |
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Keywords: | Adv, adenovirus ATA, aurintricarboxylic acid DAPI, 4&prime ,6-diamindino-2-phenylindole DCF-DA, 2&prime ,7&prime -dichlorofluorescensin diacetate DEVD-AFC, Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl coumarin DiOC6, 3,3-dihexyloxacarbocyanine iodide Emodin, 1,3,8-trihydroxy-6-methyl anthraquinone ERK, extracellular signal-regulated protein kinase HE, dihydroethidine IETD-AFC, Ile-Glu-Thr-Asp-7-amino-4-trifluoromethyl coumarin LEHD-AFC, Leu-Glu-His-Asp-7-amino-4-trifluoromethyl coumarin MAPkinase, mitogen-activated protein kinase NAC, N-acetyl-cysteine PI3 kinase, phosphatidylinositol 3&prime -kinase TUNEL, terminal transferase-mediated dUTP-fluorecensin nick end-labeling U0126, 1,4-Diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene YVAD-AFC, Tyr-Val-Ala-Asp-7-amino-4-trifluoromethyl coumarin VDVAD-AFC, Val-Asp-Val-Ala-Asp-7-amino-4-trifluoromethyl coumarin VEID-AFC, Val-Glu-Ile-Asp-7-amino-4-trifluoromethyl coumarin z-VDVAD-fmk, z-Val-Asp-Val-Ala-Asp-fluoromethyl ketone z-DEVD-fmk, z-Asp-Glu-Val-Asp-fluoromethyl ketone z-IETD-fmk, z-Ile-Glu-Thr-Asp-fluoromethyl ketone z-LEHD-fmk, z-Leu-Glu-His-Asp-fluoromethyl ketone |
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