Cancer Biology and Signal Transduction Silencing Egr1 Attenuates Radiation-Induced Apoptosis in Normal Tissues while Killing Cancer Cells and Delaying Tumor Growth

Normal tissue toxicity reduces the therapeutic index of radiotherapy and decreases the quality of life for cancer survi-vors. Apoptosis is a key element of the radiation response in normal tissues like the hippocampus and small intestine, resulting in neurocognitive disorders and intestinal malabsorp-tion. The Early Growth Response 1 (Egr1) transcription factor mediates radiation-induced apoptosis by activating the tran-scription of proapoptosis genes in response to ionizing radiation (IR). Therefore, we hypothesized that the genetic abrogation of Egr1 and the pharmacologic inhibition of its transcriptional activity could attenuate radiation-induced apo-ptosis in normal tissues. We demonstrated that Egr1-null mice had less apoptosis in the hippocampus and intestine following irradiation as compared with their wild-type littermates. A similar result was achieved using Mithramycin A (MMA) to prevent binding of Egr1 to target promoters in the mouse intestine. Abolishing Egr1 expression using shRNA dampened apoptosis and enhanced the clonogenic survival of irradiated HT22 hippocampal neuronal cells and IEC6 intestinal epithelial cells. Mechanistically, these events involved an abrogation of p53 induction by IR and an increase in the ratio of Bcl-2/Bax expres-sion. In contrast, targeted silencing of Egr1 in two cancer cell lines (GL261 glioma cells and HCT116 colorectal cancer cells) was not radioprotective, since it reduced their growth while also sensitiz-ing them to radiation-induced death. Further, Egr1 depletion delayed the growth of heterotopically implanted GL261 and HCT116 tumors. These results support the potential of silencing Egr1 in order to minimize the normal tissue complications associated with radiotherapy while enhancing tumor control.Mol Cancer Ther; 14(10); 1–10. 2015 AACR