Aberrant Glycogen Synthase Kinase 3β Is Involved in Pancreatic Cancer Cell Invasion and Resistance to Therapy

PLoS One

Yoshiharu Motoo¹  Takeo Shimasaki²  Yasuhito Ishigaki²  Yoshimichi Sai³  Mitsutoshi Nakada⁴  Yoshio Endo⁵  Kazuyuki Kawakami⁶  Toshinari Minamoto⁶  Takahisa Takino⁷  Yuri Chikano⁷  Tomomi Higashi⁷  Hiroshi Sato⁷  Ayako Kitano⁷  Mayumi Hirose⁸  Ken-ichi Miyamoto⁸ 

[1] Central Laboratory, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;Department of Hospital Pharmacy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan;Department of Hygiene, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan;Department of Medical Oncology, Kanazawa Medical University, Uchinada, Ishikawa, Japan;Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan;Division of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan

关键词: Pancreatic cancer;    Cancer treatment;    Phosphorylation;    Cancer cell migration;    Small interfering RNAs;    Ionizing radiation;    Transcription factors;    Cyclins;   

DOI  :  10.1371/journal.pone.0055289

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background and Purpose 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. Conclusion The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.

【 授权许可】

CC BY