title: Aberrant glycogen synthase kinase 3β is involved in pancreatic cancer cell invasion and resistance to therapy.
abstract: OBJECTIVE
  The 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.
  
  
  METHODS
  Pancreatic 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.
  
  
  RESULTS
  Pancreatic 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.
  
  
  CONCLUSIONS
  The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.
authors: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Ayako
authors: A
authors: Kitano
authors: Takeo
authors: T
authors: Shimasaki
authors: Yuri
authors: Y
authors: Chikano
authors: Mitsutoshi
authors: M
authors: Nakada
authors: Mayumi
authors: M
authors: Hirose
authors: Tomomi
authors: T
authors: Higashi
authors: Yasuhito
authors: Y
authors: Ishigaki
authors: Yoshio
authors: Y
authors: Endo
authors: Takahisa
authors: T
authors: Takino
authors: Hiroshi
authors: H
authors: Sato
authors: Yoshimichi
authors: Y
authors: Sai
authors: Ken-Ichi
authors: K
authors: Miyamoto
authors: Yoshiharu
authors: Y
authors: Motoo
authors: Kazuyuki
authors: K
authors: Kawakami
authors: Toshinari
authors: T
authors: Minamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy; D010766:Phosphorylation; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D000093542:Gemcitabine