Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2

Abstract Background Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. Its mechanism of action and methods of prevention remain to be investigated. Previous studies have demonstrated that ROS is responsible for As3+-induced cell transformation, which is consid...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yuan-Ye Dang, Hua Luo, Yong-Mei Li, Yang Zhou, Xiu Luo, Shui-Mu Lin, Shou-Ping Liu, Simon Ming-Yuen Lee, Chu-Wen Li, Xiao-Yan Dai
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Arsenic Curcumin Nrf2 ROS GSK-3β/β-TrCP Autophagy Other systems of medicine RZ201-999
Acceso en línea:	https://doaj.org/article/c2749398cbd344599758fae56f684e94
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c2749398cbd344599758fae56f684e94
record_format	dspace
spelling	oai:doaj.org-article:c2749398cbd344599758fae56f684e942021-11-14T12:10:21ZCurcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf210.1186/s13020-021-00527-x1749-8546https://doaj.org/article/c2749398cbd344599758fae56f684e942021-11-01T00:00:00Zhttps://doi.org/10.1186/s13020-021-00527-xhttps://doaj.org/toc/1749-8546Abstract Background Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. Its mechanism of action and methods of prevention remain to be investigated. Previous studies have demonstrated that ROS is responsible for As3+-induced cell transformation, which is considered as the first stage of As3+ carcinogenesis. The NF-E2 p45-related factor-2 (Nrf2) signaling pathway regulates the cellular antioxidant response, and activation of Nrf2 has recently been shown to limit oxidative damage following exposure to As3+ Methods and results In this study, molecular docking was used to virtually screen natural antioxidant chemical databases and identify molecules that interact with the ligand-binding site of Keap1 (PDB code 4L7B). The cell-based assays and molecular docking findings revealed that curcumin has the best inhibitory activity against Keap1-4L7B. Co-immunoprecipitation (Co-IP) results indicated that curcumin is a potent Keap1 Kelch domain-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. The increased activation of Nrf2 and its target antioxidant genes by curcumin could significantly decrease As3+-generated ROS. Moreover, curcumin induced autophagy in As3+-treated BEAS-2B via inducing autophagy by the formation of a p62/LC-3 complex and increasing autophagic flux by promoting transcription factor EB (TFEB) and lysosome-associated membrane protein 1 (LAMP1) expression. Knockdown of Nrf2 abolished curcumin-induced autophagy and downregulated ROS. Further studies showed that inhibition of autophagosome and lysosome fusion with bafilomycin a1 (BafA1) could block curcumin and prevented As3+-induced cell transformation. These results demonstrated that curcumin prevents As3+-induced cell transformation by inducing autophagy via the activation of the Nrf2 signaling pathway in BEAS-2B cells. However, overexpression of Keap-1 showed a constitutively high level of Nrf2 in As3+-transformed BEAS-2B cells (AsT) is Keap1-independent regulation. Overexpression of Nrf2 in AsT demonstrated that curcumin increased ROS levels and induced cell apoptosis via the downregulation of Nrf2. Further studies showed that curcumin decreased the Nrf2 level in AsT by activating GSK-3β to inhibit the activation of PI3K/AKT. Co-IP assay results showed that curcumin promoted the interaction of Nrf2 with the GSK-3β/β-TrCP axis and ubiquitin. Moreover, the inhibition of GSK-3β reversed Nrf2 expression in curcumin-treated AsT, indicating that the decrease in Nrf2 is due to activation of the GSK-3β/β-TrCP ubiquitination pathway. Furthermore, in vitro and in vivo results showed that curcumin induced cell apoptosis, and had anti-angiogenesis and anti-tumorigenesis effects as a result of activating the GSK-3β/β-TrCP ubiquitination pathway and subsequent decrease in Nrf2. Conclusions Taken together, in the first stage, curcumin activated Nrf2, decreased ROS, and induced autophagy in normal cells to prevent As3+-induced cell transformation. In the second stage, curcumin promoted ROS and apoptosis and inhibited angiogenesis via inhibition of constitutive expression of Nrf2 in AsT to prevent tumorigenesis. Our results suggest that antioxidant natural compounds such as curcumin can be evaluated as potential candidates for complementary therapies in the treatment of As3+-induced carcinogenesis.Yuan-Ye DangHua LuoYong-Mei LiYang ZhouXiu LuoShui-Mu LinShou-Ping LiuSimon Ming-Yuen LeeChu-Wen LiXiao-Yan DaiBMCarticleArsenicCurcuminNrf2ROSGSK-3β/β-TrCPAutophagyOther systems of medicineRZ201-999ENChinese Medicine, Vol 16, Iss 1, Pp 1-22 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arsenic Curcumin Nrf2 ROS GSK-3β/β-TrCP Autophagy Other systems of medicine RZ201-999
spellingShingle	Arsenic Curcumin Nrf2 ROS GSK-3β/β-TrCP Autophagy Other systems of medicine RZ201-999 Yuan-Ye Dang Hua Luo Yong-Mei Li Yang Zhou Xiu Luo Shui-Mu Lin Shou-Ping Liu Simon Ming-Yuen Lee Chu-Wen Li Xiao-Yan Dai Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2
description	Abstract Background Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. Its mechanism of action and methods of prevention remain to be investigated. Previous studies have demonstrated that ROS is responsible for As3+-induced cell transformation, which is considered as the first stage of As3+ carcinogenesis. The NF-E2 p45-related factor-2 (Nrf2) signaling pathway regulates the cellular antioxidant response, and activation of Nrf2 has recently been shown to limit oxidative damage following exposure to As3+ Methods and results In this study, molecular docking was used to virtually screen natural antioxidant chemical databases and identify molecules that interact with the ligand-binding site of Keap1 (PDB code 4L7B). The cell-based assays and molecular docking findings revealed that curcumin has the best inhibitory activity against Keap1-4L7B. Co-immunoprecipitation (Co-IP) results indicated that curcumin is a potent Keap1 Kelch domain-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. The increased activation of Nrf2 and its target antioxidant genes by curcumin could significantly decrease As3+-generated ROS. Moreover, curcumin induced autophagy in As3+-treated BEAS-2B via inducing autophagy by the formation of a p62/LC-3 complex and increasing autophagic flux by promoting transcription factor EB (TFEB) and lysosome-associated membrane protein 1 (LAMP1) expression. Knockdown of Nrf2 abolished curcumin-induced autophagy and downregulated ROS. Further studies showed that inhibition of autophagosome and lysosome fusion with bafilomycin a1 (BafA1) could block curcumin and prevented As3+-induced cell transformation. These results demonstrated that curcumin prevents As3+-induced cell transformation by inducing autophagy via the activation of the Nrf2 signaling pathway in BEAS-2B cells. However, overexpression of Keap-1 showed a constitutively high level of Nrf2 in As3+-transformed BEAS-2B cells (AsT) is Keap1-independent regulation. Overexpression of Nrf2 in AsT demonstrated that curcumin increased ROS levels and induced cell apoptosis via the downregulation of Nrf2. Further studies showed that curcumin decreased the Nrf2 level in AsT by activating GSK-3β to inhibit the activation of PI3K/AKT. Co-IP assay results showed that curcumin promoted the interaction of Nrf2 with the GSK-3β/β-TrCP axis and ubiquitin. Moreover, the inhibition of GSK-3β reversed Nrf2 expression in curcumin-treated AsT, indicating that the decrease in Nrf2 is due to activation of the GSK-3β/β-TrCP ubiquitination pathway. Furthermore, in vitro and in vivo results showed that curcumin induced cell apoptosis, and had anti-angiogenesis and anti-tumorigenesis effects as a result of activating the GSK-3β/β-TrCP ubiquitination pathway and subsequent decrease in Nrf2. Conclusions Taken together, in the first stage, curcumin activated Nrf2, decreased ROS, and induced autophagy in normal cells to prevent As3+-induced cell transformation. In the second stage, curcumin promoted ROS and apoptosis and inhibited angiogenesis via inhibition of constitutive expression of Nrf2 in AsT to prevent tumorigenesis. Our results suggest that antioxidant natural compounds such as curcumin can be evaluated as potential candidates for complementary therapies in the treatment of As3+-induced carcinogenesis.
format	article
author	Yuan-Ye Dang Hua Luo Yong-Mei Li Yang Zhou Xiu Luo Shui-Mu Lin Shou-Ping Liu Simon Ming-Yuen Lee Chu-Wen Li Xiao-Yan Dai
author_facet	Yuan-Ye Dang Hua Luo Yong-Mei Li Yang Zhou Xiu Luo Shui-Mu Lin Shou-Ping Liu Simon Ming-Yuen Lee Chu-Wen Li Xiao-Yan Dai
author_sort	Yuan-Ye Dang
title	Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2
title_short	Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2
title_full	Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2
title_fullStr	Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2
title_full_unstemmed	Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2
title_sort	curcumin prevents as3+-induced carcinogenesis through regulation of gsk3β/nrf2
publisher	BMC
publishDate	2021
url	https://doaj.org/article/c2749398cbd344599758fae56f684e94
work_keys_str_mv	AT yuanyedang curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT hualuo curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT yongmeili curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT yangzhou curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT xiuluo curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT shuimulin curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT shoupingliu curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT simonmingyuenlee curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT chuwenli curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2 AT xiaoyandai curcuminpreventsas3inducedcarcinogenesisthroughregulationofgsk3bnrf2
_version_	1718429429283160064

Curcumin prevents As3+-induced carcinogenesis through regulation of GSK3β/Nrf2

Ejemplares similares