Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: association with kinase activity and tumor dedifferentiation.

Abstract

PURPOSE:

We have shown recently that glycogen synthase kinase-3 (GSK-3) beta regulates nuclear factor-kappaB (NF-kappaB)-mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3beta in pancreatic cancer cells and assess the antitumor effect of GSK-3 inhibition in vivo to improve our understanding of the mechanism by which GSK-3beta affects NF-kappaB activity in pancreatic cancer.

EXPERIMENTAL DESIGN:

Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3beta in human pancreatic tumors. We studied the effect of GSK-3 inhibition on tumor growth, cancer cell proliferation, and survival in established CAPAN2 tumor xenografts using a tumor regrowth delay assay, Western blotting, bromodeoxyuridine incorporation, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

RESULTS:

We found nuclear accumulation of GSK-3beta in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3beta nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3beta can accumulate in the nucleus of pancreatic cancer cells and that inhibition of GSK-3 kinase activity represses its nuclear accumulation via proteasomal degradation within the nucleus. Lastly, we have found that inhibition of GSK-3 arrests pancreatic tumor growth in vivo and decreases NF-kappaB-mediated pancreatic cancer cell survival and proliferation in established tumor xenografts.

CONCLUSIONS:

Our results show the antitumor effect of GSK-3 inhibition in vivo, identify GSK-3beta nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3beta regulates NF-kappaB activity in pancreatic cancer.

• Authors: Andrei V Ougolkov, Martin E Fernandez-Zapico, Vladimir N Bilim, Thomas C Smyrk, Suresh T Chari, Daniel D Billadeau
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 17 Pg. 5074-81 (Sep 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16951223 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Thiazoles
• N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
• Urea
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Adenocarcinoma (drug therapy, enzymology, metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, enzymology, metabolism)
• Cell Proliferation (drug effects)
• Female
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, biosynthesis, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Male
• Mice
• Mice, Nude
• Middle Aged
• NF-kappa B (metabolism)
• Pancreatic Neoplasms (drug therapy, enzymology, metabolism)
• Structure-Activity Relationship
• Survival Rate
• Thiazoles (administration & dosage, pharmacology)
• Transplantation, Heterologous
• Urea (administration & dosage, analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays