Mini-ReviewNF-κB modulation and ionizing radiation: mechanisms and future directions for cancer treatment
Introduction
NF-κB (Nuclear Factor-κB) was described for the first time in 1986 as a nuclear protein binding to the kappa immunoglobulin-light chain enhancer [1]. Since then, NF-κB has emerged as an ubiquitous factor involved in the regulation of numerous important processes as diverses as immune [2] and inflammatory responses [3], apoptosis [4] and cell proliferation [5]. These last two properties explain the implication of NF-κB in the tumorigenic process as well as the promise of a targeted therapeutic intervention [6]. In the present study, we described in the first part an overview of structure and functions of NF-κB and, in a second part, a focus on ionizing radiation, its impact on NF-κB pathway and the capacity of radiosensitization of NF-κB.
Section snippets
Structure of NF-κB /IKB complexes
Rel/NF-κB transcription factors share a highly conserved 300-amino-acid Rel Homology Domain (RH) containing sequences for dimerization, DNA binding, nuclear translocation and interaction with the inhibitory subunit IKB (Inhibitor of κB) [7], [8]. Rel/NF-κB are organized in two classes. The p105 and p100 proteins of the NF-κB class are synthesized as precursors containing several C-terminal ankyrin repeats that are eliminated during maturation to respectively generate DNA-binding competent
Regulation of NF-κB activity
NF-κB activation is modulated by various different mechanisms involving protein/protein interactions, phosphorylation, and transcriptional modulation.
NF-κB functions
Since its discovery in 1986, NF-κB has primarily been known for its regulatory role for immune and inflammatory responses. Its functions have now been extended to the regulation of cell proliferation and survival and NF-κB is considered as both an important player in the tumorigenic process and a potential therapeutic target in cancer [5], [41], [42].
NF-κB and radioresistance
Radiotherapy acts through the induction of double strand breaks to DNA in order to induce elimination of cancerous cells via programmed cell death [68].
The efficiency of radiotherapy for cancer treatment is limited by toxic side effects impeding dose escalation. Moreover, cancer cells often develop radioresistance mechanisms that are related to the DNA repair response. The aim of combining chemo- to radio-therapy is to strengthen the efficiency of radiation by inhibition of DNA repair, and
Conclusion
NF-κB is now recognized as an important player in several critical steps of the tumorigenic process. Not only NF-κB promotes survival of cancer cells but it also contributes to abnormal proliferation and metastasis. As a stress factor, NF-κB is a crucial element of the cell's protective response to radiations and represents therefore an attractive target in new therapeuticals approaches to fight cancer. The pharmaceutical industry is producing several inhibitors of the NF-κB pathway that are
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