There are now more than 10 million cancer survivors in the United States. With these numbers, chronic sequelae that result from
cancer therapy have become a major health care problem. Although
radiation therapy of the brain has improved
cancer cure rates,
learning disorders and
memory deficits are a common consequence of this
therapy. Here we show that
glycogen synthase kinase 3beta (GSK-3beta) is required for radiation-induced hippocampal neuronal apoptosis and subsequent neurocognitive decline. Inhibition of
GSK-3beta either by small molecules (
SB216763 or
SB415286) or by ectopic expression of
kinase-inactive
GSK-3beta before irradiation significantly attenuated radiation-induced apoptosis in hippocampal neurons.
GSK-3beta inhibition with
SB216763 or
SB415286 also decreased apoptosis in the subgranular zone of the hippocampus in irradiated mice, leading to improved cognitive function in irradiated animals. Studies of the molecular mechanisms of the cytoprotective effect showed that
GSK-3beta activity in hippocampal neurons was not significantly altered by radiation, pointing to the indirect involvement of this
enzyme in radiation-induced apoptosis. At the same time, radiation led to increased accumulation of p53, whereas inhibition of the basal level of
GSK-3beta activity before radiation prevented p53 accumulation, suggesting a possible mechanism of cytoprotection by
GSK-3beta inhibitors. These findings identify
GSK-3beta signaling as a key regulator of radiation-induced damage in hippocampal neurons and suggest that
GSK-3beta inhibitors may have a therapeutic role in protecting both pediatric and adult
cancer patients and may help to improve quality of life in cancer survivors.