Role of PI3K/Akt signaling in TRAIL- and radiation-induced gastrointestinal apoptosis.

Activation of the PI3K/Akt pathway is associated with tumorigenesis and resistance to apoptosis and ionizing radiation (IR). We sought to characterize the effects of physiologic and genetic manipulation of Akt signaling on IR-induced gastrointestinal (GI) apoptosis in mice. PI3K/Akt signaling is stimulated by insulin. We evaluated the time course of Akt stimulation by insulin and found it overlapped with protection from apoptosis induced by TRAIL (TNFalpha Related Apoptosis Inducing Ligand) in cell lines. Mice were treated with insulin and glucose and the kinetics of in vivo Akt stimulation were determined by phospho-Akt (S473) (P-Akt) immunofluorescence in the gut. Irradiation of mice by five Gy at 30 minutes after insulin/glucose administration induced apoptosis in the crypts of the ileum and colon after six hours, but induced little apoptosis in the liver or esophagus. Pre-treatment with insulin and glucose did not significantly alter levels of IR-induced apoptosis in the gut. IR alone led to sustained increases in P-Akt in the gut at six hours, a protective response that may have precluded additional protection from insulin/glucose. In Akt1-/- mice, there was significantly more apoptosis in ileum crypts of irradiated mice compared to Akt1+/+ mice, suggesting a role for the pathway in the GI tract in response to IR. Taken together, modulation of the PI3K/Akt pathway may sensitize or protect against cancer therapies in both tumor and normal tissues.