1. Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.
- Author
-
Zhou, G, Yu, J, Wang, A, Liu, S-H, Sinnett-Smith, J, Wu, J, Sanchez, R, Nemunaitis, J, Ricordi, C, Rozengurt, E, and Brunicardi, FC
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Digestive Diseases ,Diabetes ,Cancer ,Orphan Drug ,Rare Diseases ,Pancreatic Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Adenocarcinoma ,Carcinoma ,Pancreatic Ductal ,Cell Line ,Cell Line ,Tumor ,Diabetes Mellitus ,Type 2 ,Down-Regulation ,Epidermal Growth Factor ,Extracellular Signal-Regulated MAP Kinases ,Genes ,Homeobox ,HEK293 Cells ,Homeodomain Proteins ,Humans ,MAP Kinase Signaling System ,Metformin ,Pancreas ,Pancreatic Neoplasms ,Protein Kinase Inhibitors ,Signal Transduction ,Trans-Activators ,EGF ,ERK ,metformin ,PDAC ,PDX-1 ,signaling ,Medicinal and Biomolecular Chemistry ,Pharmacology and Pharmaceutical Sciences ,Immunology ,Medicinal and biomolecular chemistry - Abstract
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.
- Published
- 2016