O3-001 - Aberrant Glycogen Synthase Kinase 3βIS Involved in Pancreatic Cancer Cell Invasion and Resistance to Therapy

Abstract

ABSTRACT Purpose The major obstacles to effective treatment of pancreatic cancer are the highly invasive nature of this tumor type and its resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine protein kinase that regulates multiple cellular pathways and has been implicated in various diseases including cancer. Here we investigate a putative pathological role for aberrant GSK3β in the highly invasive and treatment resistant phenotype of pancreatic cancer. Methods Pancreatic cancer cell lines were examined for GSK3β expression, phosphorylation and activity using western bloting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Results Pancreatic cancer cells showed increased expression and deregulated activity of GSK3β that were associated with changes in its differential phosphorylation. Inhibition of GSK3β reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their chemotactic migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac-1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the attenuation of cancer cell migration and invasion, reduced secretion of matrix metalloproteinase-2 and decreased phosphorylation of focal adhesion kinase. Conclusion The targeting of GSK3β may represent a novel and effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.