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

S. Umar, S. Sarkar, S. Cowey, P. Singh

Research output: Contribution to journalArticle

29 Scopus citations

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 IκBα (IKKα/β), inhibitor of κB (IκB)α and p65NF-κB was significantly elevated in proximal colonic crypts of Fabp-PG versus wild-type mice, which was associated with degradation of IκBα 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-κB (NF-κB) activation), demonstrating for the first time a critical role of NF-κB in mediating hyperproliferative affects of PG on colonic crypts of Fabp-PG mice, in vivo. Thus, downregulation of NF-κB may significantly reduce the increased risk of colon carcinogenesis in response to PG.

Original languageEnglish (US)
Pages (from-to)5599-5611
Number of pages13
JournalOncogene
Volume27
Issue number42
DOIs
StatePublished - Sep 18 2008

Keywords

  • Annexin II
  • ERKs
  • Fabp-PG mice
  • NEMO
  • NFκB
  • Progastrin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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