Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis

• Published in: Biomedicine & pharmacotherapy Vol. 125; p. 109999
• Main Authors: Tao, Xufeng, Chen, Qing, Li, Ning, Xiang, Hong, Pan, Yue, Qu, Yueyang, Shang, Dong, Go, Vay Liang W., Xue, Jing, Sun, Yongwei, Zhang, Zhigang, Guo, Junchao, Xiao, Gary Guishan
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.05.2020; Elsevier
• Subjects: Acinar Cells - metabolism; Acinar Cells - pathology; Acinar-to-ductal metaplasia; Animals; Biomarkers; Carcinoma, Pancreatic Ductal - etiology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Transformation, Neoplastic - metabolism; Ceruletide - adverse effects; Chronic pancreatitis; Disease Models, Animal; Gene Expression Regulation; Immunohistochemistry; Metaplasia; Mice; Pancreatitis, Chronic - etiology; Pancreatitis, Chronic - metabolism; Pancreatitis, Chronic - pathology; PDAC; PSCs; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Serotonin; Serotonin - metabolism; Signal Transduction; TPH1; ROCK; IHC; TGFs; ADM; EGFR; CK19; α-SMA; DMEM; NF-κB; Rac1; Que; Acinar-to-ductal metaplasia; Serotonin; Chronic pancreatitis; CP; ECM; RhoA; AP; PDAC; PSCs; AB/PAS; PanIN; IPA; ELISA
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.109999

[Display omitted] •5-HT level in pancreatic tissues increases in caerulein-induced CP mice.•5-HT promotes ADM formation and PSCs activation in vitro and in vivo.•5-HT promotes ADM and pancreatic fibrosis by regulating RhoA/ROCK signaling.•Quercetin inhibits CP induced-ADM and -fibrosis via inhibiting 5-HT release. The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.