Activation of NF-[kappa]B is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo.
Umar, S 1,3; Sarkar, S 2,3; Cowey, S 2; Singh, P 2
[Article] Oncogene. 27(42):5599-5611, September 18, 2008.

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: 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 I[kappa]B[alpha] (IKK[alpha]/[beta]), inhibitor of [kappa]B (I[kappa]B)a and p65NF-[kappa]B was significantly elevated in proximal colonic crypts of Fabp-PG versus wild-type mice, which was associated with degradation of I[kappa]B[alpha] 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 colocalized 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-[kappa]B (NF-[kappa]B) activation), demonstrating for the first time a critical role of NF-[kappa]B in mediating hyperproliferative affects of PG on colonic crypts of Fabp-PG mice, in vivo. Thus, downregulation of NF-[kappa]B may significantly reduce the increased risk of colon carcinogenesis in response to PG.

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