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Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis

Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been reported by us and others to display potent antitumor effects. However, the molecular target of grifolin has not been identified and the underlying mechanism of action is not full...

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Autores principales: Luo, Xiangjian, Yang, Lifang, Xiao, Lanbo, Xia, Xiaofeng, Dong, Xin, Zhong, Juanfang, Liu, Ying, Li, Namei, Chen, Ling, Li, Hongde, Li, Wei, Liu, Wenbin, Yu, Xinfang, Chen, Hanyong, Tang, Min, Weng, Xinxian, Yi, Wei, Bode, Ann, Dong, Zigang, Liu, Jikai, Cao, Ya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767464/
https://www.ncbi.nlm.nih.gov/pubmed/26516701
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author Luo, Xiangjian
Yang, Lifang
Xiao, Lanbo
Xia, Xiaofeng
Dong, Xin
Zhong, Juanfang
Liu, Ying
Li, Namei
Chen, Ling
Li, Hongde
Li, Wei
Liu, Wenbin
Yu, Xinfang
Chen, Hanyong
Tang, Min
Weng, Xinxian
Yi, Wei
Bode, Ann
Dong, Zigang
Liu, Jikai
Cao, Ya
author_facet Luo, Xiangjian
Yang, Lifang
Xiao, Lanbo
Xia, Xiaofeng
Dong, Xin
Zhong, Juanfang
Liu, Ying
Li, Namei
Chen, Ling
Li, Hongde
Li, Wei
Liu, Wenbin
Yu, Xinfang
Chen, Hanyong
Tang, Min
Weng, Xinxian
Yi, Wei
Bode, Ann
Dong, Zigang
Liu, Jikai
Cao, Ya
author_sort Luo, Xiangjian
collection PubMed
description Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been reported by us and others to display potent antitumor effects. However, the molecular target of grifolin has not been identified and the underlying mechanism of action is not fully understood. Here, we report that the ERK1/2 protein kinases are direct molecular targets of grifolin. Molecular modeling, affinity chromatography and fluorescence quenching analyses showed that grifolin directly binds to ERK1/2. And in vitro and ex vivo kinase assay data further demonstrated that grifolin inhibited the kinase activities of ERK1/2. We found that grifolin suppressed adhesion, migration and invasion of high-metastatic cancer cells. The inhibitory effect of grifolin against tumor metastasis was further confirmed in a metastatic mouse model. We found that grifolin decreased phosphorylation of Elk1 at Ser383, and the protein as well as the mRNA level of DNMT1 was also down-regulated. By luciferase reporter and ChIP assay analyses, we confirmed that grifolin inhibited the transcription activity of Elk1 as well as its binding to the dnmt1 promoter region. Moreover, we report that significant increases in the mRNA levels of Timp2 and pten were induced by grifolin. Thus, our data suggest that grifolin exerts its anti-tumor activity by epigenetic reactivation of metastasis inhibitory-related genes through ERK1/2-Elk1-DNMT1 signaling. Grifolin may represent a promising therapeutic lead compound for intervention of cancer metastasis, and it may also be useful as an ERK1/2 kinase inhibitor as well as an epigenetic agent to further our understanding of DNMT1 function.
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spelling pubmed-47674642016-03-25 Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis Luo, Xiangjian Yang, Lifang Xiao, Lanbo Xia, Xiaofeng Dong, Xin Zhong, Juanfang Liu, Ying Li, Namei Chen, Ling Li, Hongde Li, Wei Liu, Wenbin Yu, Xinfang Chen, Hanyong Tang, Min Weng, Xinxian Yi, Wei Bode, Ann Dong, Zigang Liu, Jikai Cao, Ya Oncotarget Research Paper Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been reported by us and others to display potent antitumor effects. However, the molecular target of grifolin has not been identified and the underlying mechanism of action is not fully understood. Here, we report that the ERK1/2 protein kinases are direct molecular targets of grifolin. Molecular modeling, affinity chromatography and fluorescence quenching analyses showed that grifolin directly binds to ERK1/2. And in vitro and ex vivo kinase assay data further demonstrated that grifolin inhibited the kinase activities of ERK1/2. We found that grifolin suppressed adhesion, migration and invasion of high-metastatic cancer cells. The inhibitory effect of grifolin against tumor metastasis was further confirmed in a metastatic mouse model. We found that grifolin decreased phosphorylation of Elk1 at Ser383, and the protein as well as the mRNA level of DNMT1 was also down-regulated. By luciferase reporter and ChIP assay analyses, we confirmed that grifolin inhibited the transcription activity of Elk1 as well as its binding to the dnmt1 promoter region. Moreover, we report that significant increases in the mRNA levels of Timp2 and pten were induced by grifolin. Thus, our data suggest that grifolin exerts its anti-tumor activity by epigenetic reactivation of metastasis inhibitory-related genes through ERK1/2-Elk1-DNMT1 signaling. Grifolin may represent a promising therapeutic lead compound for intervention of cancer metastasis, and it may also be useful as an ERK1/2 kinase inhibitor as well as an epigenetic agent to further our understanding of DNMT1 function. Impact Journals LLC 2015-10-26 /pmc/articles/PMC4767464/ /pubmed/26516701 Text en Copyright: © 2015 Luo et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Luo, Xiangjian
Yang, Lifang
Xiao, Lanbo
Xia, Xiaofeng
Dong, Xin
Zhong, Juanfang
Liu, Ying
Li, Namei
Chen, Ling
Li, Hongde
Li, Wei
Liu, Wenbin
Yu, Xinfang
Chen, Hanyong
Tang, Min
Weng, Xinxian
Yi, Wei
Bode, Ann
Dong, Zigang
Liu, Jikai
Cao, Ya
Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
title Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
title_full Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
title_fullStr Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
title_full_unstemmed Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
title_short Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
title_sort grifolin directly targets erk1/2 to epigenetically suppress cancer cell metastasis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767464/
https://www.ncbi.nlm.nih.gov/pubmed/26516701
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