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褪黑素，一种新型的选择性ATF - 6抑制剂，通过下调COX - 2诱导人肝癌细胞凋亡。

Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation.

作者信息

Bu Li-Jia, Yu Han-Qing, Fan Lu-Lu, Li Xiao-Qiu, Wang Fang, Liu Jia-Tao, Zhong Fei, Zhang Cong-Jun, Wei Wei, Wang Hua, Sun Guo-Ping

机构信息

Li-Jia Bu, Han-Qing Yu, Lu-Lu Fan, Xiao-Qiu Li, Fang Wang, Jia-Tao Liu, Fei Zhong, Cong-Jun Zhang, Hua Wang, Guo-Ping Sun, Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.

出版信息

World J Gastroenterol. 2017 Feb 14;23(6):986-998. doi: 10.3748/wjg.v23.i6.986.

DOI:10.3748/wjg.v23.i6.986
PMID:28246472
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5311108/
Abstract

AIM

To clarify the mechanisms involved in the critical endoplasmic reticulum (ER) stress initiating unfolded protein response pathway modified by melatonin.

METHODS

Hepatoma cells, HepG2, were cultured . Flow cytometry and TUNEL assay were used to measure HepG2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes' expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis.

RESULTS

In the present study, we first identified that melatonin selectively blocked activating transcription factor 6 (ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 siRNA contributed the enhanced HepG2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed.

CONCLUSION

These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis.

摘要

目的

阐明褪黑素修饰的内质网（ER）应激引发未折叠蛋白反应途径所涉及的机制。

方法

培养肝癌细胞HepG2。采用流式细胞术和TUNEL检测法检测HepG2细胞凋亡情况。分别采用蛋白质印迹法和定量逆转录-聚合酶链反应法测定ER应激和凋亡相关基因表达的蛋白质和信使核糖核酸水平。通过免疫组织化学分析验证患者组织芯片的构建。

结果

在本研究中，我们首先确定褪黑素选择性阻断活化转录因子6（ATF-6），然后抑制环氧合酶-2（COX-2）表达，导致内质网应激条件下肝癌细胞凋亡增强。在衣霉素（一种内质网应激诱导剂）刺激下，褪黑素或ATF-6小干扰RNA显著增加CCAAT增强子结合蛋白同源蛋白水平、抑制COX-2并降低Bcl-2/Bax比值，从而导致HepG2细胞凋亡增强。在临床肝细胞癌患者中，进一步证实了ATF-6与COX-2之间的密切关系。

结论

这些发现表明，褪黑素作为一种新型的选择性ATF-6抑制剂，可以使人类肝癌细胞对内质网应激诱导的凋亡敏感。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/bd806ab69b62/WJG-23-986-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/44d57ac619ca/WJG-23-986-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/ee2fe4a5a4ba/WJG-23-986-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/c3f521517560/WJG-23-986-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/15117e8d4e58/WJG-23-986-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/bd806ab69b62/WJG-23-986-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/44d57ac619ca/WJG-23-986-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/ed40b3a0fc67/WJG-23-986-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/ec4a99a769d1/WJG-23-986-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/ee2fe4a5a4ba/WJG-23-986-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/c3f521517560/WJG-23-986-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/15117e8d4e58/WJG-23-986-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eebc/5311108/bd806ab69b62/WJG-23-986-g007.jpg

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本文引用的文献

1
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2
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Oncol Lett. 2016 Jul;12(1):231-237. doi: 10.3892/ol.2016.4605. Epub 2016 May 18.
3
Endoplasmic reticulum stress eIF2α-ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney.
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MedComm (2020). 2025 Jun 19;6(7):e70263. doi: 10.1002/mco2.70263. eCollection 2025 Jul.
4
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Adv Sci (Weinh). 2025 Mar;12(10):e2412378. doi: 10.1002/advs.202412378. Epub 2025 Jan 10.
5
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Metabolomics. 2024 Apr 19;20(3):46. doi: 10.1007/s11306-024-02112-3.
6
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Cell Death Dis. 2016 Jun 2;7(6):e2251. doi: 10.1038/cddis.2016.78.
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6
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7
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8
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