Aberrant nuclear accumulation of glycogen synthase kinase-3β in human pancreatic cancer:: Association with kinase activity and tumor dedifferentiation

Purpose: We have shown recently that glycogen synthase kinase-3 (GSK-3) beta regulates nuclear factor-kappa B (NF-kappa B) - mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3 beta 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-3 beta affects NF-kappa B activity in pancreatic cancer. Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3 beta 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-3 beta in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3 beta nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3 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-kappa B-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-3 nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3 beta regulates NF-kappa B activity in pancreatic cancer.