ERK activation is required for CCK-mediated pancreatic adaptive growth in mice

Am J Physiol Gastrointest Liver Physiol. 2014 Oct 1;307(7):G700-10. doi: 10.1152/ajpgi.00163.2014. Epub 2014 Aug 7.


High levels of cholecystokinin (CCK) can stimulate pancreatic adaptive growth in which mature acinar cells divide, leading to enhanced pancreatic mass with parallel increases in protein, DNA, RNA, and digestive enzyme content. Prolonged release of CCK can be induced by feeding trypsin inhibitor (TI) to disrupt normal feedback control. This leads to exocrine growth in a CCK-dependent manner. The extracellular signal-related kinase (ERK) pathway regulates many proliferative processes in various tissues and disease models. The aim of this study was to evaluate the role of ERK signaling in pancreatic adaptive growth using the MEK inhibitors PD-0325901 and trametinib (GSK-1120212). It was determined that PD-0325901 given two times daily by gavage or mixed into powdered chow was an effective and specific inhibitor of ERK signaling in vivo. TI-containing chow led to a robust increase in pancreatic mass, protein, DNA, and RNA content. This pancreatic adaptive growth was blocked in mice fed chow containing the MEK inhibitors. PD-0325901 blocked TI-induced ERK-regulated early response genes, cell-cycle proteins, and mitogenesis by acinar cells. It was determined that ERK signaling is necessary for the initiation of pancreatic adaptive growth but not necessary to maintain it. PD-0325901 blocked adaptive growth when given before cell-cycle initiation but not after mitogenesis had been established. Furthermore, GSK-1120212, a chemically distinct inhibitor of the ERK pathway that is now approved for clinical use, inhibited growth similar to PD-0325901. These data demonstrate that the ERK pathway is required for CCK-stimulated pancreatic adaptive growth.

Keywords: GSK-1120212; PD-0325901; cholecystokinin; extracellular signal-related kinase; mitogen-activated protein kinase; mitogen/extracellular signal-regulated kinase inhibitors; pancreatic growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation* / drug effects
  • Cholecystokinin / metabolism*
  • DNA Replication
  • Early Growth Response Transcription Factors / metabolism
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • MAP Kinase Signaling System* / drug effects
  • Male
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Pancreas / drug effects
  • Pancreas / enzymology*
  • Pancreas / growth & development
  • Protein Kinase Inhibitors / pharmacology
  • RNA / biosynthesis
  • Time Factors
  • Trypsin Inhibitors / pharmacology


  • Cell Cycle Proteins
  • Early Growth Response Transcription Factors
  • Protein Kinase Inhibitors
  • Trypsin Inhibitors
  • RNA
  • Cholecystokinin
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases