GSK-3 as potential target for therapeutic irvention in cancer

James A. Mccubrey, Linda S. Steelman, Fred E. Bertrand, Nicole M. Davis, Melissa Sokolosky, Steve L. Abrams, Giuseppe Montalto, Antonino B. D'Assoro, Massimo Libra, Ferdinando Nicoletti, Roberta Maestro, Jorg Basecke, Dariusz Rakus, Agnieszka Gizak, Zoya Demidenko, Lucio Cocco, Alberto M. Martelli, Melchiorre Cervello

Research output: Contribution to journalArticle

259 Scopus citations

Abstract

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.

Original languageEnglish (US)
Pages (from-to)2881-2911
Number of pages31
JournalOncotarget
Volume5
Issue number10
DOIs
StatePublished - 2014

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Keywords

  • Akt
  • Cancer stem cells
  • GSK-3
  • Hedgehog
  • MTOR
  • Mutations
  • Notch
  • PI3K
  • Rapamycin
  • Targeted therapy
  • Therapy resistance
  • Wnt/beta-catenin

ASJC Scopus subject areas

  • Oncology

Cite this

Mccubrey, J. A., Steelman, L. S., Bertrand, F. E., Davis, N. M., Sokolosky, M., Abrams, S. L., Montalto, G., D'Assoro, A. B., Libra, M., Nicoletti, F., Maestro, R., Basecke, J., Rakus, D., Gizak, A., Demidenko, Z., Cocco, L., Martelli, A. M., & Cervello, M. (2014). GSK-3 as potential target for therapeutic irvention in cancer. Oncotarget, 5(10), 2881-2911. https://doi.org/10.18632/oncotarget.2037