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

Abstract

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 (TNF-alpha 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 5 Gy at 30 min after insulin/glucose administration induced apoptosis in the crypts of the ileum and colon after 6 hrs, 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 6 hrs, 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.