Mechanisms of Radiomitigative Cell Signaling Via Lysophosphatidic Acid Receptors

Radiomitigators attenuate radiation injury when administered after irradiation. Lysophosphatidic acid (LPA) a lipid mediator rescues apoptotically condemned cells. LPA protects IEC‐6 intestinal epithelial cells in vitro and intestinal crypts in vivo from radiation‐induced apoptosis. Using KO mice and cells we established that the LPA2 receptor is required for radiomitigation. Through its C‐terminal PDZ and LIM‐binding motifs LPA2 forms agonist‐dependent macromolecular signaling complexes. LPA2 interacts with the proapoptotic protein Siva‐1 and targets it for proteasomal degradation. Full activation of the NFkB and ERK1/2 prosurvival pathway requires formation of an LPA2, NHERF2, and TRIP‐6 ternary macromolecular complex. These signals inhibit the mitochondrial apoptosis pathway. Reconstitution of the LPA2 receptor into MEFs derived from LPA1/2 KO mice restores radioprotection. Conditioned medium from irradiated U937 cells induces bystander apoptosis in non‐irradiated IEC‐6 cultures and LPA2‐transfected MEFs. Using in silico drug discovery we found a novel LPA2‐selective agonist GRI977143 that protects cells from radiation‐ and chemotherapy‐induced apoptosis. GRI977143 also increases the survival of mice exposed to lethal levels of radiation. Supported by AI08405.