Abstract
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.
Highlights
Oral submucous fibrosis (OSF) is a pre-cancerous lesion related to chewing areca nut
Primary normal (BMFs were isolated from oral submucous fibrosis tissues and identified; transforming growth factor-β1 (TGF-β1) stimulation was conducted to activate the buccal mucosal fibroblast (BMF), as confirmed by TGF-β1 signaling activation and increases in α-smooth muscle actin(α-SMA) and Collagen Type I Alpha 1 Chain (Col1A1) protein levels
BMFs were isolated from oral submucous fibrosis tissues and treated with 5 ng/ml TGF-β1 for 0, 24, and 48 h for BMFs activation, which was identified by increased Vimentin content as revealed by immunofluorescent staining (IF) staining (Figure 1A)
Summary
Oral submucous fibrosis (OSF) is a pre-cancerous lesion related to chewing areca nut (betel quid). This custom is common among people in South Asia and has spread to Europe and North America. Chang et al (Chang et al, 2014) revealed that several molecules, including plasminogen activator inhibitor-1 (Yang et al, 2003), insulin-like growth factor-1 (IGF1) (Tsai et al, 2005), and nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) (Ni et al, 2007), could be expressed in human buccal mucosal fibroblasts (BMFs) after treatment with arecoline. The specific molecular mechanism by which arecoline affects the OSF remains unclear
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