摘要
胰腺导管腺癌(PDAC)是最强大并且最危险的疾病之一,患者平均只有3-5个月的生存期限由于只有先进的阶段诊断和无效的治疗方案的组合。二甲双胍(1,1-二甲基双胍盐酸盐),用于2型糖尿病的主要药物,成为PDAC和其他人类癌症的潜在治疗方法。二甲双胍通过多种腺苷一磷酸(AMP)激活的蛋白激酶(AMPK)依赖性和/或AMPK独立的机制发挥其抗癌作用。我们目前的数据来显示二甲双胍抑制胰腺转录因子胰十二指肠同源盒-1(PDX-1),提示二甲双胍发挥其抗肿瘤作用的一个潜在的新机制。二甲双胍抑制PDX-1的表达在mRNA和蛋白水平,以及在PDAC细胞PDX-1的转录活性。细胞外信号调节激酶(ERK)被确定为一个PDX-1相互作用蛋白质通过在GFP-PDX-1稳定的HEK293细胞的抗体阵列筛选。ERK1和PDX-1基因共转染导致在剂量依赖性HEK293细胞中的一个增强的PDX-1表达。免疫沉淀/免疫印迹分析证实在PANC-1细胞被表皮生长因子刺激的 ERK-PDX-1相互作用。EGF诱导增强PANC-1细胞PDX-1表达这种刺激被MEK抑制剂PD0325901抑制。二甲双胍抑制EGF刺激PDX-1的表达并伴随着抑制ERK激酶的激活PANC-1细胞。总之,我们的研究表明,在PDAC细胞二甲双胍中PDX-1是一个潜在的新目标,二甲双胍可能发挥其抗肿瘤作用在PDAC下调PDX-1基因通过一种机制涉及抑制ERK信号。
关键词: EGF,ERK,二甲双胍,PDAC,PDX-1,信号。
Current Molecular Medicine
Title:Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.
Volume: 16 Issue: 1
Author(s): G. Zhou, J. Yu, A. Wang, S.-H. Liu, J. Sinnett-Smith, J. Wu, R. Sanchez, J. Nemunaitis and C. Ricordi, E. Rozengurt and F.C. Brunicardi
Affiliation:
关键词: EGF,ERK,二甲双胍,PDAC,PDX-1,信号。
摘要: Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.
Export Options
About this article
Cite this article as:
G. Zhou, J. Yu, A. Wang, S.-H. Liu, J. Sinnett-Smith, J. Wu, R. Sanchez, J. Nemunaitis and C. Ricordi, E. Rozengurt and F.C. Brunicardi , Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma., Current Molecular Medicine 2016; 16 (1) . https://dx.doi.org/10.2174/1566524016666151222145551
DOI https://dx.doi.org/10.2174/1566524016666151222145551 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Nonalcoholic Fatty Liver Disease In Children: Recent Practice Guidelines, Where Do They Take Us?
Current Pediatric Reviews Editorial (Hot Topic: Hypertension: A Serious Complication in Pregnancy)
Current Hypertension Reviews Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen
Current Neuropharmacology Postponing Motherhood: A Demographic and Contemporary Issue
Current Women`s Health Reviews Family History of Type 2 Diabetes: Does Having a Diabetic Parent Increase the Risk?
Current Diabetes Reviews Biomarker Assessment in Nutritional Modulation of Oxidative Stress-Induced Cancer Development by Lipid-Related Bioactive Molecules
Recent Patents on Anti-Cancer Drug Discovery Physical Activity and Insulin Resistance
Current Nutrition & Food Science Obesity: The Metabolic Disease, Advances on Drug Discovery and Natural Product Research
Current Topics in Medicinal Chemistry Outcomes of Treatment and Predictors of Response to Sofosbuvir Plus Simeprevir in Hepatitis C Virus with Genotype-4 Infection
Infectious Disorders - Drug Targets Subject Index To Volume 2
Current Nutrition & Food Science Potassium Channels and Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia
Current Vascular Pharmacology Moxifloxacin-induced Hypoglycemia in a Non-diabetic Patient
Current Drug Safety A Glycation Angle to Look into the Diabetic Vasculopathy: Cause and Cure
Current Vascular Pharmacology Proteochemometrics for the Prediction of Binding to the MHC Proteins
Letters in Drug Design & Discovery Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar?
Current Drug Targets Salvianolic Acid A Attenuates Cell Apoptosis, Oxidative Stress, Akt and NF-κB Activation in Angiotensin-II Induced Murine Peritoneal Macrophages
Current Pharmaceutical Biotechnology Lipoprotein(a): Current Perspectives
Current Vascular Pharmacology Functional Genome and Proteome Analyses of Cutaneous Autoimmune Diseases
Current Pharmaceutical Design Role of Microfluidics in Blood-Brain Barrier Permeability Cell Culture Modeling: Relevance to CNS Disorders
CNS & Neurological Disorders - Drug Targets How to Make a Non-Antigenic Protein (Auto) Antigenic: Molecular Complementarity Alters Antigen Processing and Activates Adaptive-Innate Immunity Synergy
Anti-Cancer Agents in Medicinal Chemistry