Disruption of the PI3K axis abrogates ionizing radiation‐induced cell death

Abstract

Effective and safe therapies are lacking to abrogate the lethal effects of accidental or intentional public exposure to toxic doses of ionizing radiation. Our recent unbiased phenotypic screen using a sentinel human pluripotent cell line and a small interfering RNA (siRNA) library targeting druggable genes implicated the phosphoinositide‐3‐kinase (PI3K) pathway in cellular death after ionizing radiation. Using a model of embryonic stem cells, we now demonstrate that the prototype PI3K inhibitor LY294002 as well a new PI3K inhibitor class EMF388–021 mitigated the lethal effects of ionizing radiation including the induction of apoptosis. Moreover, a single intraperitoneal dose of LY294002 (30 mg/kg) given 4 or 24 h after 9.25 Gy of total body irradiation significantly reduced death. Similarly, a single intraperitoneal dose of EMF388–021 (10 mg/kg) given 4 h after 9.25 Gy of ionizing radiation markedly reduced lethality. We found PI3K inhibition stimulated radiation‐induced autophagic flux and reduced mitochondrial respiration providing potential mechanisms for the radiation mitigation. This study documents that an unbiased siRNA assay can assist in the identification of pharmacologically useful radiation mitigators and implicates the PI3K pathway in the human radiation response.