Journal
CURRENT MOLECULAR MEDICINE
Volume 16, Issue 1, Pages 83-90Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1566524016666151222145551
Keywords
EGF; ERK; metformin; PDAC; PDX-1; signaling
Categories
Funding
- CURE: Digestive Disease Research Center [P30DK41301]
- National Institutes of Health (NIH) [NIDDK R01-DK46441, NCI R01-CA095731]
- Ann and Jerry Moss Foundation
- Department of Veterans Affair Grant [1I01BX001473]
- [P01 CA163200]
- [P30 DK4130]
- [R01 DK100405]
- NATIONAL CANCER INSTITUTE [R01CA095731, P01CA163200] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK100405, R56DK046441, P30DK041301, R01DK046441] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX001473] Funding Source: NIH RePORTER
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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 down-regulated 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.
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