Glycine-extended gastrin inhibits apoptosis in colon cancer cells via separate activation of Akt and JNK pathways

Mol Cell Endocrinol. 2006 Mar 9;247(1-2):140-9. doi: 10.1016/j.mce.2005.12.050. Epub 2006 Jan 27.

Abstract

Glycine-extended gastrin (G-Gly) is produced by colon cancers and has growth promoting and anti-apoptotic effects in the colonic epithelium. We have examined the anti-apoptotic effects of G-Gly and the signal transduction pathways involved. G-Gly stimulated HT-29 cell proliferation in a concentration dependent manner and inhibited serum-starvation and celecoxib-induced apoptosis. Inhibition of signalling via c-Jun NH2-terminal kinase (JNK) with SP600125 or PI3-kinase/Akt with LY294002 abolished the effects of G-Gly. G-Gly significantly increased phosphorylation of both JNK and Akt. The JAK2 inhibitor AG490 abolished the anti-apoptotic effect of G-Gly and inhibited phosphorylation of Akt but not of JNK. G-Gly stimulated tyrosine phosphorylation of JAK2. G-Gly-increased activation of AP-1 was JNK-dependant and activation of STAT3 was JAK2-dependant. We conclude that G-Gly promotes growth and inhibits apoptosis in colon cancer cells. These effects are mediated via the JAK2, PI3-kinase/Akt and JNK pathways. Activation of JAK2 is upstream of Akt but not of JNK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / pharmacology
  • Apoptosis / drug effects*
  • Celecoxib
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromones / pharmacology
  • Colonic Neoplasms
  • Gastrins / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Janus Kinase 2
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology*
  • Pyrazoles / pharmacology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Tyrosine / metabolism
  • Tyrphostins / pharmacology

Substances

  • Anthracenes
  • Chromones
  • Gastrins
  • Morpholines
  • Proto-Oncogene Proteins
  • Pyrazoles
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Sulfonamides
  • Transcription Factor AP-1
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • glycine-extended gastrin 17
  • pyrazolanthrone
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Janus Kinase 2
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Celecoxib