NF-kappa B-mediated adaptive resistance to ionizing radiation

Abstract

Ionizing radiation (IR) began to be a powerful medical modality soon after Wilhelm Röntgen's discovery of X-rays in 1895. Today, more than 50% of cancer patients receive radiotherapy at some time during the course of their disease. Recent technical developments have significantly increased the precision of dose delivery to the target tumor, making radiotherapy more efficient in cancer treatment. However, tumor cells have been shown to acquire a radioresistance that has been linked to increased recurrence and failure in many patients. The exact mechanisms by which tumor cells develop an adaptive resistance to therapeutic fractional irradiation are unknown, although low-dose IR has been well defined for radioadaptive protection of normal cells. This review will address the radioadaptive response, emphasizing recent studies of molecular-level reactions. A prosurvival signaling network initiated by the transcription factor NF-kappa B, DNA-damage sensor ATM, oncoprotein HER-2, cell cyclin elements (cyclin B1), and mitochondrial functions in radioadaptive resistance is discussed. Further elucidation of the key elements in this prosurvival network may generate novel targets for resensitizing the radioresistant tumor cells.

Fig. 1

Schematic representations of NF-κB/Rel proteins, their regulators, and posttranslational modification sites of NF-κB p65/RelA. (A) Structures of the mammalian NF-κB, IκB, and IKK proteins. The number of amino acids in each protein is indicated on the right. Presumed sites of cleavage for p105/NF-κB1 (amino acid 433) and p100/NF-κB2 (amino acid 447) are shown on the top of each protein. The positions of functional domains are indicated, including the Rel homology domain (RHD), DNA binding domain (DBD), dimerization domain (DM), nuclear localization signal (NLS), transactivation domains (TD), glycine-rich hinge region (GGG), ankyrin repeats (ANK), double serine phosphorylation sites (SS), leucine zipper (LZ), helix-loop-helix (HLH), NEMO-binding domain (NBD), α-helix (H), coiled coil (CC), and zinc finger (Z). (B) Phosphorylation and acetylation sites within NF-κB p65. Six inducible phosphorylation and five acetylation sites have been identified in the NF-B p65 subunit. The known kinases and target residues include PKC-ζ (protein kinase C-ζ), MSK1 (mitogen or stress-activated kinase 1), PKA (protein kinase A), CKII (casein kinase II), GSK-3β (glycogen synthase kinase-3β), CaMKIV (calmodulin-dependent kinase IV), RSKI (ribosomal S6 kinase), TBK1 [TANK (TRAF family member-associated NF-κB activator)-binding kinase 1], PCAF (p300/CBP-associated factor), CBP (CREB-binding protein).

Fig. 2

Schematic presentation of the NF-κB signaling network in radiation-induced adaptive radioresistance. Fractional ionizing radiation can directly induce DNA damage causing double-strand breaks (DSB) and single-strand breaks (SSB). The damaged DNA activates nuclear ATM, which in turn translocates to the cytoplasm to activate NF-κB via regulation of IKK activity, resulting in the dissociation of IκB from the complex and then activation of NF-κB. The reactive oxygen species (ROS) generated in cells by IR not only induce DNA damage in the nucleus but also activate NF-κB via the TRAFs pathway. Therefore, NF-κB activation by both nuclear and cytoplasmic pathways seems to be necessary for up-regulation of IR-effector genes that include at least partial antiapoptotic and cell cycle elements. The NF-κB effector genes have been shown to be necessary for an enhanced cell survival when the irradiated cells are exposed again to IR. In addition, the mitochondrial antioxidant enzyme MnSOD, which detoxifies superoxide free radicals in mitochondria, is regulated by NF-κB, which may play a key role in the regulation of the cell cycle and apoptosis, although the exact mechanism is to be elucidated.