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Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis
- Source :
- Biomedicine & Pharmacotherapy, Vol 125, Iss, Pp 109999-(2020)
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Serotonin
RHOA
RM1-950
Acinar Cells
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Fibrosis
Metaplasia
Pancreatitis, Chronic
medicine
Animals
Acinar-to-ductal metaplasia
Pharmacology
rho-Associated Kinases
biology
Chemistry
PDAC
General Medicine
PSCs
medicine.disease
Immunohistochemistry
digestive system diseases
Disease Models, Animal
030104 developmental biology
Cell Transformation, Neoplastic
Gene Expression Regulation
030220 oncology & carcinogenesis
Hepatic stellate cell
Cancer research
biology.protein
Pancreatitis
Therapeutics. Pharmacology
Signal transduction
medicine.symptom
rhoA GTP-Binding Protein
Chronic pancreatitis
Biomarkers
Ceruletide
Carcinoma, Pancreatic Ductal
Signal Transduction
Subjects
Details
- ISSN :
- 19506007
- Volume :
- 125
- Database :
- OpenAIRE
- Journal :
- Biomedicinepharmacotherapy = Biomedecinepharmacotherapie
- Accession number :
- edsair.doi.dedup.....5e5729eaf514a906e6783869c239ef63