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Glycogen synthase kinase-3[beta] is a pivotal mediator of cancer invasion and resistance to therapy

Cancer science, 2016-10, Vol.107 (10), p.1363-1372 [Peer Reviewed Journal]

ISSN: 1347-9032 ;EISSN: 1349-7006 ;DOI: 10.1111/cas.13028

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  • Title:
    Glycogen synthase kinase-3[beta] is a pivotal mediator of cancer invasion and resistance to therapy
  • Author: Domoto, Takahiro ; Pyko, Ilya V ; Furuta, Takuya ; Miyashita, Katsuyoshi ; Uehara, Masahiro ; Shimasaki, Takeo ; Nakada, Mitsutoshi ; Minamoto, Toshinari
  • Is Part Of: Cancer science, 2016-10, Vol.107 (10), p.1363-1372
  • Description: 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)-3[beta] is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3[beta] 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 GSK3[beta]. This review focuses on the role of GSK3[beta] 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 GSK3[beta] 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 GSK3[beta] in sustaining tumor cell survival and proliferation underpins the targeting of GSK3[beta] 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 GSK3[beta] as a molecular hub that integrates distinct biological pathways.
  • Language: English
  • Identifier: ISSN: 1347-9032
    EISSN: 1349-7006
    DOI: 10.1111/cas.13028
  • Source: Wiley Open Access Journals
    PubMed Central
    ProQuest Central
    DOAJ Directory of Open Access Journals
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