NF-kappa B signaling pathway as a target for human tumor radiosensitization

NF-kappa B is a critical nuclear transcriptional factor that is activated in response to cellular stresses and regulates the expression of genes involved in cell proliferation and cell death. When regulated NF-kappa B activation is disrupted, cells undergo apoptosis. That is, constitutively elevated or dysregulated NF-kappa B activation leads to cell death in response to stress. These mechanisms have been shown experimentally by expressing dominant negative inhibitors of NF-kappa B (I kappa B-alpha) in cancer cells exposed to chemotherapeutic agents or to ionizing radiation. NF-kappa B also plays an important role in a novel, radiation-inducible signaling pathway that involves the ataxia-telangiectasia mutated (ATM) protein kinase. Cells from patients with ataxia-telangiectasia (AT) are exquisitely sensitive to ionizing radiation and exhibit impaired NF-kappa B activation in response to this stress. Restoration of NF-kappa B regulation in AT fibroblasts by introducing a dominant negative form of I kappa B-alpha has resulted in correction of radiation sensitivity and a reduction of ionizing radiation-induced apoptosis. Expression of introduced ATM in AT cells results in correction of NF-kappa B regulation and an increase in postradiation survival without reduction in radiation-induced apoptosis. Taken together, these observations support a central role for NF-kappa B regulation in cellular intrinsic radiation sensitivity and apoptosis after exposure to ionizing radiation. Therefore, we hypothesize that the signaling pathway involving ATM/NF-kappa B/I kappa B offers attractive potential molecular targets for radiation sensitization in strategies to enhance the therapeutic ratio in cancer treatment.