Wu Chunhua, Qiu Shanhu, Zhu Xiangyun, Lin Hao, Li Ling
Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
Cell Physiol Biochem. 2018;47(4):1711-1720. doi: 10.1159/000491003. Epub 2018 Jun 27.
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.
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.
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.
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.
背景/目的：据报道，二甲双胍治疗与2型糖尿病患者胰腺癌（PC）的较低发病率和死亡率相关。活化的胰腺星状细胞（PSC）是负责胰腺纤维化和PC进展的关键基质细胞。然而，关于二甲双胍对PSC的影响的研究很少。鉴于二甲双胍对PC的潜在有益作用，胰腺肿瘤基质是新疗法的重要靶点。我们观察了二甲双胍对PSC的影响。我们研究了二甲双胍对人PSC增殖和细胞外基质（ECM）蛋白产生的影响。
用不同浓度的二甲双胍（0 - 10 mmol/L）培养细胞。通过免疫荧光染色检测核Ki67标记来确定细胞增殖。通过定量实时聚合酶链反应、免疫印迹和免疫荧光显微镜研究ECM的产生。研究了负责二甲双胍作用的重要调节分子单磷酸腺苷激活蛋白激酶（AMPK）以及被认为是二甲双胍药理作用最重要转运体的有机阳离子转运体成员1（OCT1），探讨它们是否可能参与二甲双胍诱导的增殖和ECM产生。
我们的结果表明，二甲双胍通过激活AMPK磷酸化抑制PSC增殖并减少ECM蛋白的产生。OCT1表达的沉默导致二甲双胍对PSC活性的影响降低。
总体而言，数据表明OCT1可能有助于摄取二甲双胍并调节PSC活性。OCT1是二甲双胍调节PSC活性的靶点。
