Glycogen Synthase Kinase 3ß in Cancer Biology and Treatment.

ABSTRACT

Glycogen synthase kinase (GSK)3ß is a multifunctional serine/threonine protein kinase with more than 100 substrates and interacting molecules. GSK3ß is normally active in cells and negative regulation of GSK3ß activity via phosphorylation of its serine 9 residue is required for most normal cells to maintain homeostasis. Aberrant expression and activity of GSK3ß contributes to the pathogenesis and progression of common recalcitrant diseases such as glucose intolerance, neurodegenerative disorders and cancer. Despite recognized roles against several proto-oncoproteins and mediators of the epithelial-mesenchymal transition, deregulated GSK3ß also participates in tumor cell survival, evasion of apoptosis, proliferation and invasion, as well as sustaining cancer stemness and inducing therapy resistance. A therapeutic effect from GSK3ß inhibition has been demonstrated in 25 different cancer types. Moreover, there is increasing evidence that GSK3ß inhibition protects normal cells and tissues from the harmful effects associated with conventional cancer therapies. Here, we review the evidence supporting aberrant GSK3ß as a hallmark property of cancer and highlight the beneficial effects of GSK3ß inhibition on normal cells and tissues during cancer therapy. The biological rationale for targeting GSK3ß in the treatment of cancer is also discussed at length.