EDITORIALS

Radiosensitivity and Transcription Factor NF-{kappa}B Inhibition—Progress and Pitfalls

Anatoly Dritschilo

Correspondence to: Anatoly Dritschilo, M.D., Department of Radiation Medicine, Georgetown University Medical Center, TRB E202A-B, 3970 Reservoir Rd., N.W., Washington, DC 20007 (e-mail: dritscha{at}gunet.georgetown.edu).

Cellular responses to ionizing radiation include activation of signal transduction cascades that may originate at the plasma membrane, cytoplasm, or nucleus. The cell's success in dealing with radiation "stress" determines its survival or death. Activation of transcription factor NF-{kappa}B, an immediate early response after exposure to ionizing radiations, functions to protect cells from apoptosis (programmed cell death), but the role of NF-{kappa}B in mitotic cell death has not been fully defined (1,2). NF-{kappa}B is constitutively activated in lymphoid cells, immortal ataxia telangiectasia (AT) fibroblasts, and other cells (3-6). Activation of NF-{kappa}B after ionizing radiation requires intact ATM gene function in AT fibroblasts (7). Because AT fibroblasts exhibit dysregulated NF-{kappa}B activation and extreme radiation sensitivity, it is reasonable to ask if radiation responses of tumor cells can be modified by inhibiting NF-{kappa}B.

NF-{kappa}B/Rel transcription factors are activated by a variety of different signals in pathways that converge on the phosphorylation and degradation of I{kappa}Bs, inhibitors of NF-{kappa}B. This results in the unmasking of the nuclear localization signals that lead to translocation of NF-{kappa}B/Rel dimers into the nucleus. Five known mammalian NF-{kappa}B/Rel proteins include c-Rel, p65 (RelA), RelB, p50 (NF-{kappa}B1), and p52 (NF-{kappa}B2) that bind DNA as homodimers or heterodimers (8). It should also be noted that p50-p65/I{kappa}B is not the only complex relevant to NF-{kappa}B activation. The p50-p65 heterodimer can interact with other I{kappa}B family members, and NF-{kappa}B can also exist in other homodimer or heterodimer complexes, such as p50-p50 and p65-p65 (8). Furthermore, the I{kappa}B family consists of three members—I{kappa}B{alpha}, I{kappa}Bß, and I{kappa}B{epsilon}. In addition, the carboxyl-terminal regions of the precursors for p50 and p52, p105 and p100, respectively, can also function as inhibitory proteins. These inhibitors respond differentially to NF-{kappa}B-inducing signals in a cell type-dependent and stimulus-dependent manner in vivo (9).

In this issue of the Journal, Pajonk et al. (10) report that activation of NF-{kappa}B does not determine the intrinsic radiosensitivity of cancer cells. Cells were transduced with an adenoviral vector expressing a mutant form of I{kappa}B{alpha}, an inhibitor of NF-{kappa}B. The resultant clonogenicity of cells transduced with mutant I{kappa}B{alpha} was markedly reduced to 7.4% (compared with 29.5% for control cells), and the apoptotic index was 90%. Therefore, subsequent radiation survival experiments were done on relatively small subsets of cells, whereas biochemical assays were done on mostly apoptotic cells.

It is unusual to see publication of essentially negative studies in the Journal. However, there is potential value if definitive data can provide direction for other scientists in the field. Clinically, intrinsic radiation sensitivity has been implicated in tumor curability (11). The ability to manipulate radiation sensitivity offers a potential strategy for improving the therapeutic ratio in cancer treatment. Therefore, an examination of the experimental results and data interpretation underlying the negative radiobiologic conclusions of Pajonk et al. (10) are appropriate.

In summary, the findings of Pajonk et al. (10) should be interpreted with caution. These data show that mutant I{kappa}B{alpha} expression in these cells results in cell death by apoptosis. What they do not provide is insight into the role of NF-{kappa}B regulation in intrinsic radiation sensitivity.

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