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Aberrant Nuclear Accumulation of Glycogen Synthase Kinase-3ß in Human Pancreatic Cancer: Association with Kinase Activity and Tumor Dedifferentiation

Authors' Affiliations: ¹ Division of Oncology Research, ² Gastrointestinal Unit, ³ Department of Laboratory Medicine and Pathology, and ⁴ Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota and ⁵ Department of Urology, Yamagata University School of Medicine, Yamagata, Japan

Requests for reprints: Daniel D. Billadeau, Department of Immunology and Division of Oncology Research, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-266-4334; Fax: 507-266-5146; E-mail: billadeau.daniel{at}mayo.edu.

Purpose: We have shown recently that glycogen synthase kinase-3 (GSK-3) ß regulates nuclear factor-B (NF-B)–mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3ß 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-3ß affects NF-B activity in pancreatic cancer.

Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3ß 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-3ß in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3ß nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3ß 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-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-3ß nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3ß regulates NF-B activity in pancreatic cancer.

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