Abstract
Background and PurposeThe major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer.MethodsPancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting 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. Effects of GSK3β inhibition on cancer cell xenografts were also examined.ResultsPancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their 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 Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts.ConclusionThe targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.
Highlights
Pancreatic cancer is a major health problem due to an overall 5year survival rate of less than 10% [1]
Cancer cell-derived Glycogen synthase kinase 3b (GSK3b) was active for phosphorylation of its substrate, b-catenin (Fig. 1B)
These results indicate that pancreatic cancer cells express active GSK3b that is not regulated by differential phosphorylation at S9 and Y216
Summary
Pancreatic cancer is a major health problem due to an overall 5year survival rate of less than 10% [1]. It is characterized by the highly proliferative and invasive capacity of the tumor cells and a strong predisposition for metastasis [2,3,4]. Novel therapeutic strategies that enhance the effects of gemcitabine and attenuate the invasive properties of pancreatic cancer cells are needed. The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. We investigate a pathological role for GSK3b in the invasive and treatment resistant phenotype of pancreatic cancer
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