Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma

Abstract We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive ac...

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Autores principales:	Wenjun Zeng, Chunyun Zhang, Hongwei Cheng, Yun-Long Wu, Jie Liu, Zekun Chen, Jian-gang Huang, Russell Erick Ericksen, Liqun Chen, Haiping Zhang, Alice Sze Tsai Wong, Xiao-kun Zhang, Weiping Han, Jin-Zhang Zeng
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fb891e945fc34ac6a9a63bf9fdf367da
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spelling	oai:doaj.org-article:fb891e945fc34ac6a9a63bf9fdf367da2021-12-02T11:52:41ZTargeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma10.1038/s41598-017-00233-52045-2322https://doaj.org/article/fb891e945fc34ac6a9a63bf9fdf367da2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00233-5https://doaj.org/toc/2045-2322Abstract We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.Wenjun ZengChunyun ZhangHongwei ChengYun-Long WuJie LiuZekun ChenJian-gang HuangRussell Erick EricksenLiqun ChenHaiping ZhangAlice Sze Tsai WongXiao-kun ZhangWeiping HanJin-Zhang ZengNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wenjun Zeng Chunyun Zhang Hongwei Cheng Yun-Long Wu Jie Liu Zekun Chen Jian-gang Huang Russell Erick Ericksen Liqun Chen Haiping Zhang Alice Sze Tsai Wong Xiao-kun Zhang Weiping Han Jin-Zhang Zeng Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
description	Abstract We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.
format	article
author	Wenjun Zeng Chunyun Zhang Hongwei Cheng Yun-Long Wu Jie Liu Zekun Chen Jian-gang Huang Russell Erick Ericksen Liqun Chen Haiping Zhang Alice Sze Tsai Wong Xiao-kun Zhang Weiping Han Jin-Zhang Zeng
author_facet	Wenjun Zeng Chunyun Zhang Hongwei Cheng Yun-Long Wu Jie Liu Zekun Chen Jian-gang Huang Russell Erick Ericksen Liqun Chen Haiping Zhang Alice Sze Tsai Wong Xiao-kun Zhang Weiping Han Jin-Zhang Zeng
author_sort	Wenjun Zeng
title	Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
title_short	Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
title_full	Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
title_fullStr	Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
title_full_unstemmed	Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
title_sort	targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/fb891e945fc34ac6a9a63bf9fdf367da
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Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma

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