Activation of NF-kappaB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo

Oncogene. 2008 Sep 18;27(42):5599-611. doi: 10.1038/onc.2008.169. Epub 2008 Jun 2.

Abstract

Mice overexpressing progastrin (PG) in intestinal mucosa (fatty acid-binding protein (Fabp)-PG mice) are at an increased risk of proximal colon carcinogenesis in response to azoxymethane. Here, we report a significant increase in the length of proximal colonic crypts in Fabp-PG mice, associated with potent antiapoptotic effects of PG, which likely contributed to the previously reported increase in colon carcinogenesis in Fabp-PG mice. Phosphorylation of kinase of IkappaBalpha (IKKalpha/beta), inhibitor of kappaB (IkappaB)alpha and p65NF-kappaB was significantly elevated in proximal colonic crypts of Fabp-PG versus wild-type mice, which was associated with degradation of IkappaBalpha and nuclear translocation/activation of p65. Surprisingly, distal colonic crypt cells were not as responsive to elevated levels of PG in Fabp-PG mice. Annexin II, recently described as a high-affinity receptor for PG, strongly co-localized with PG intracellularly and on basolateral membranes of proximal crypt cells, providing evidence that annexin-II binds PG in situ in colonic crypt cells. Proliferative and antiapoptotic effects of PG on proximal crypts of Fabp-PG mice were attenuated to wild-type levels, on treatment with NEMO peptide (an inhibitor of nuclear factor-kappaB (NF-kappaB) activation), demonstrating for the first time a critical role of NF-kappaB in mediating hyperproliferative affects of PG on colonic crypts of Fabp-PG mice, in vivo. Thus, downregulation of NF-kappaB may significantly reduce the increased risk of colon carcinogenesis in response to PG.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Annexin A2 / analysis
  • Apoptosis*
  • Cell Proliferation
  • Colon / metabolism
  • Colon / pathology*
  • Colonic Neoplasms / etiology*
  • DNA / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fatty Acid-Binding Proteins / physiology
  • Gastrins / analysis
  • Gastrins / physiology*
  • I-kappa B Proteins / metabolism
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / physiology*
  • Phosphorylation
  • Protein Precursors / analysis
  • Protein Precursors / physiology*
  • Transcription Factor RelA / analysis

Substances

  • Annexin A2
  • Fatty Acid-Binding Proteins
  • Gastrins
  • I-kappa B Proteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • Protein Precursors
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • big gastrin
  • DNA
  • Extracellular Signal-Regulated MAP Kinases