SN52, a novel nuclear factor-κB inhibitor, blocks nuclear import of RelB:p52 dimer and sensitizes prostate cancer cells to ionizing radiation

Abstract

The activation of nuclear factor-kappaB (NF-kappaB) is thought to protect cancer cells against therapy-induced cytotoxicity. RelB, a member of the NF-kappaB family in the alternative pathway, is uniquely expressed at a high level in prostate cancer with high Gleason scores. Here, we show that ionizing radiation (IR) enhances nuclear import of RelB, leading to up-regulation of its target gene, manganese superoxide dismutase (MnSOD), and renders prostate cancer cells resistant to IR. To selectively block RelB nuclear import, we designed a cell-permeable SN52 peptide, a variant of the SN50 peptide that has been shown to block nuclear import of NF-kappaB family members in the classic pathway. Inhibition of IR-induced NF-kappaB activation by SN50 and SN52 was achieved by selectively interrupting the association of p50 and p52 with nuclear import factors importin-alpha1 and importin-beta1. Importantly, SN52 seems to be more efficient for radiosensitization of prostate cancer cells at clinically relevant radiation doses and has less cytotoxicity to normal prostate epithelial cells compared with the toxicity observed with SN50. These results suggest that targeting the alternative pathway is a promising approach to selectively radiosensitize prostate cancers and that SN52 may serve as a prototype biological agent for sensitizing prostate cancers to clinically relevant doses of IR.