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Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells

Background: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, espec...

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Autores principales: Hsieh, Yung-Yu, Lee, Ko-Chao, Cheng, Kung-Chuan, Lee, Kam-Fai, Yang, Ya-Ling, Chu, Hsin-Tung, Lin, Ting-Wei, Chen, Chin-Chu, Hsieh, Meng-Chiao, Huang, Cheng-Yi, Kuo, Hsing-Chun, Teng, Chih-Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045953/
https://www.ncbi.nlm.nih.gov/pubmed/36979011
http://dx.doi.org/10.3390/antiox12030764
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author Hsieh, Yung-Yu
Lee, Ko-Chao
Cheng, Kung-Chuan
Lee, Kam-Fai
Yang, Ya-Ling
Chu, Hsin-Tung
Lin, Ting-Wei
Chen, Chin-Chu
Hsieh, Meng-Chiao
Huang, Cheng-Yi
Kuo, Hsing-Chun
Teng, Chih-Chuan
author_facet Hsieh, Yung-Yu
Lee, Ko-Chao
Cheng, Kung-Chuan
Lee, Kam-Fai
Yang, Ya-Ling
Chu, Hsin-Tung
Lin, Ting-Wei
Chen, Chin-Chu
Hsieh, Meng-Chiao
Huang, Cheng-Yi
Kuo, Hsing-Chun
Teng, Chih-Chuan
author_sort Hsieh, Yung-Yu
collection PubMed
description Background: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear. Methods: The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V–FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation. Results: Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo.
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spelling pubmed-100459532023-03-29 Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells Hsieh, Yung-Yu Lee, Ko-Chao Cheng, Kung-Chuan Lee, Kam-Fai Yang, Ya-Ling Chu, Hsin-Tung Lin, Ting-Wei Chen, Chin-Chu Hsieh, Meng-Chiao Huang, Cheng-Yi Kuo, Hsing-Chun Teng, Chih-Chuan Antioxidants (Basel) Article Background: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear. Methods: The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V–FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation. Results: Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo. MDPI 2023-03-21 /pmc/articles/PMC10045953/ /pubmed/36979011 http://dx.doi.org/10.3390/antiox12030764 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hsieh, Yung-Yu
Lee, Ko-Chao
Cheng, Kung-Chuan
Lee, Kam-Fai
Yang, Ya-Ling
Chu, Hsin-Tung
Lin, Ting-Wei
Chen, Chin-Chu
Hsieh, Meng-Chiao
Huang, Cheng-Yi
Kuo, Hsing-Chun
Teng, Chih-Chuan
Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
title Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
title_full Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
title_fullStr Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
title_full_unstemmed Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
title_short Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
title_sort antrodin c isolated from antrodia cinnamomea induced apoptosis through ros/akt/erk/p38 signaling pathway and epigenetic histone acetylation of tnfα in colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045953/
https://www.ncbi.nlm.nih.gov/pubmed/36979011
http://dx.doi.org/10.3390/antiox12030764
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