OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

Cellular Physiology and Biochemistry

Chunhua Wu¹ 

关键词: Metformin;    Pancreatic stellate cells;    Proliferation;    Phosphorylated AMPK;    Organic cation transporter member 1;   

DOI  :  10.1159/000491003

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

【 授权许可】

CC BY-NC-ND