Glycogen synthase kinase‐3β is a pivotal mediator of cancer invasion and resistance to therapy

• Published in: Cancer science Vol. 107; no. 10; pp. 1363 - 1372
• Main Authors: Domoto, Takahiro, Pyko, Ilya V., Furuta, Takuya, Miyashita, Katsuyoshi, Uehara, Masahiro, Shimasaki, Takeo, Nakada, Mitsutoshi, Minamoto, Toshinari
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2016; John Wiley and Sons Inc
• Subjects: Alzheimer's disease; Animals; Cancer; Cancer therapies; Cell adhesion & migration; Cell cycle; Cell proliferation; Chemotherapy; Clinical trials; Drug Resistance, Neoplasm - genetics; Enzyme Activation; Gene Expression; Genotype & phenotype; Glioblastoma; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - chemistry; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Growth factors; GSK3β; Humans; Immortalization; invasion; Invasiveness; Isoenzymes; Kinases; Medical research; Metastasis; Molecular Targeted Therapy; Morphology; Motility; Neoplasm Invasiveness; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Pancreatic cancer; Phenotype; Phenotypes; Radiation therapy; Radiation Tolerance - genetics; Review; Therapeutic applications; therapeutic target; therapy resistance; Tumor cells; Tumors; GSK3β; therapeutic target; invasion; Cancer; therapy resistance
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13028

Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)‐3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro‐invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on the role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. Tumor invasion and therapy resistance are inextricably linked to each other in refractory cancer, thereby presenting challenges to current cancer treatment paradigms. Increasing evidence of an unexpected role for GSK3β in sustaining tumor cell survival and proliferation underpins the targeting of GSK3β as a novel cancer treatment. This review provides new insights into the unwanted association between cancer invasion and therapy resistance by focusing on previously unrecognized functions of GSK3β as a molecular hub that integrates distinct biological pathways.