Takeo Shimasaki1, Ayako Kitano2, Yoshiharu Motoo3, Toshinari Minamoto2
1Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University and Hospital, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293; Division of Translational and Clinical Oncology, Cancer Research Institute and Cancer Center, Kanazawa University and Hospital, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
2Division of Translational and Clinical Oncology, Cancer Research Institute and Cancer Center, Kanazawa University and Hospital, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
3Department of Medical Oncology, Kanazawa Medical University and Hospital, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
Development and progression of pancreatic cancer involves general metabolic disorder, local chronic inflammation, and multistep activation of distinct oncogenic molecular pathways. These pathologic processes result in a highly invasive and metastatic tumor phenotype that is a major obstacle to curative surgical intervention, infusional gemcitabine-based chemotherapy, and radiation therapy. Many clinical trials with chemical compounds and therapeutic antibodies targeting growth factors, angiogenic factors, and matrix metalloproteinases have failed to demonstrate definitive therapeutic benefits to refractory pancreatic cancer patients. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target in common chronic and progressive diseases, including cancer. Here we review accumulating evidence for a pathologic role of GSK3β in promoting tumor cell survival, proliferation, invasion, and resistance to chemotherapy and radiation in pancreatic cancer. We also discuss the putative involvement of GSK3β in mediating metabolic disorder, local inflammation, and molecular alteration leading to pancreatic cancer development. Taken together, we highlight potential therapeutic as well as preventive effects of GSK3β inhibition in pancreatic cancer.
Keywords: Carcinogenesis, GSK3β, pancreatic cancer, tumor progression.