Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway

Chewing areca nut (betel quid) is strongly associated with oral submucous fibrosis (OSF), a pre-cancerous lesion. Among the areca alkaloids, arecoline is the main agent responsible for fibroblast proliferation; however, the specific molecular mechanism of arecoline affecting the OSF remains unclear....

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Autores principales:	Bo Zhang, Lihua Gao, Chunsheng Shao, Mingsi Deng, Liangjian Chen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	oral submucous fibrosis buccal mucosal fibroblast arecoline PDE4A cAMP-Epac1 signaling pathway Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/121ff120c728473386b7f2ac33c6d661
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spelling	oai:doaj.org-article:121ff120c728473386b7f2ac33c6d6612021-11-08T05:36:04ZArecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway1663-981210.3389/fphar.2021.722040https://doaj.org/article/121ff120c728473386b7f2ac33c6d6612021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.722040/fullhttps://doaj.org/toc/1663-9812Chewing areca nut (betel quid) is strongly associated with oral submucous fibrosis (OSF), a pre-cancerous lesion. Among the areca alkaloids, arecoline is the main agent responsible for fibroblast proliferation; however, the specific molecular mechanism of arecoline affecting the OSF remains unclear. The present study revealed that arecoline treatment significantly enhanced Transforming growth factor-β (TGF-β)-induced buccal mucosal fibroblast (BMF) activation and fibrotic changes. Arecoline interacts with phosphodiesterase 4A (PDE4A) to exert its effects through modulating PDE4A activity but not PDE4A expression. PDE4A silence reversed the effects of arecoline on TGF-β-induced BMFs activation and fibrotic changes. Moreover, the exchange protein directly activated by cAMP 1 (Epac1)-selective Cyclic adenosine 3′,5′-monophosphate (cAMP) analog (8-Me-cAMP) but not the protein kinase A (PKA)-selective cAMP analog (N6-cAMP) remarkably suppressed α-smooth muscle actin(α-SMA) and Collagen Type I Alpha 1 Chain (Col1A1) protein levels in response to TGF-β1 and arecoline co-treatment, indicating that cAMP-Epac1 but not cAMP-PKA signaling is involved in arecoline functions on TGF-β1-induced BMFs activation. In conclusion, arecoline promotes TGF-β1-induced BMFs activation through enhancing PDE4A activity and the cAMP-Epac1 signaling pathway during OSF. This novel mechanism might provide more powerful strategies for OSF treatment, requiring further in vivo and clinical investigation.Bo ZhangLihua GaoChunsheng ShaoMingsi DengLiangjian ChenFrontiers Media S.A.articleoral submucous fibrosisbuccal mucosal fibroblastarecolinePDE4AcAMP-Epac1 signaling pathwayTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	oral submucous fibrosis buccal mucosal fibroblast arecoline PDE4A cAMP-Epac1 signaling pathway Therapeutics. Pharmacology RM1-950
spellingShingle	oral submucous fibrosis buccal mucosal fibroblast arecoline PDE4A cAMP-Epac1 signaling pathway Therapeutics. Pharmacology RM1-950 Bo Zhang Lihua Gao Chunsheng Shao Mingsi Deng Liangjian Chen Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway
description	Chewing areca nut (betel quid) is strongly associated with oral submucous fibrosis (OSF), a pre-cancerous lesion. Among the areca alkaloids, arecoline is the main agent responsible for fibroblast proliferation; however, the specific molecular mechanism of arecoline affecting the OSF remains unclear. The present study revealed that arecoline treatment significantly enhanced Transforming growth factor-β (TGF-β)-induced buccal mucosal fibroblast (BMF) activation and fibrotic changes. Arecoline interacts with phosphodiesterase 4A (PDE4A) to exert its effects through modulating PDE4A activity but not PDE4A expression. PDE4A silence reversed the effects of arecoline on TGF-β-induced BMFs activation and fibrotic changes. Moreover, the exchange protein directly activated by cAMP 1 (Epac1)-selective Cyclic adenosine 3′,5′-monophosphate (cAMP) analog (8-Me-cAMP) but not the protein kinase A (PKA)-selective cAMP analog (N6-cAMP) remarkably suppressed α-smooth muscle actin(α-SMA) and Collagen Type I Alpha 1 Chain (Col1A1) protein levels in response to TGF-β1 and arecoline co-treatment, indicating that cAMP-Epac1 but not cAMP-PKA signaling is involved in arecoline functions on TGF-β1-induced BMFs activation. In conclusion, arecoline promotes TGF-β1-induced BMFs activation through enhancing PDE4A activity and the cAMP-Epac1 signaling pathway during OSF. This novel mechanism might provide more powerful strategies for OSF treatment, requiring further in vivo and clinical investigation.
format	article
author	Bo Zhang Lihua Gao Chunsheng Shao Mingsi Deng Liangjian Chen
author_facet	Bo Zhang Lihua Gao Chunsheng Shao Mingsi Deng Liangjian Chen
author_sort	Bo Zhang
title	Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway
title_short	Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway
title_full	Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway
title_fullStr	Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway
title_full_unstemmed	Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway
title_sort	arecoline enhances phosphodiesterase 4a activity to promote transforming growth factor-β-induced buccal mucosal fibroblast activation via camp-epac1 signaling pathway
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/121ff120c728473386b7f2ac33c6d661
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Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway

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