title: Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.
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.
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: A
authors.initials: A
authors.lastname: Wang
authors.forename: S-H
authors.initials: SH
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Sinnett-Smith
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Sanchez
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: C
authors.initials: C
authors.lastname: Ricordi
authors.forename: E
authors.initials: E
authors.lastname: Rozengurt
authors.affiliation: Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, USA. cbrunicardi@mednet.ucla.edu.
authors.forename: F C
authors.initials: FC
authors.lastname: Brunicardi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D005801:Genes, Homeobox / Q000187:drug effects; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004815:Epidermal Growth Factor; D008687:Metformin; D048049:Extracellular Signal-Regulated MAP Kinases