The transcription factor nuclear factor-κB (NF-κB) family includes RelA (p65), RelB, c-Rel, NF-κB1 (p50/p105), and NF-κB2 (p52/p100). It regulates expression of numerous genes involved in immune response, inflammation, cell survival, and cancer. The NF-κB dimers are retained as inactive forms in cytoplasm by inhibitors that mask the nuclear translocation sequences (NLS) found in the Rel homology domain. In mammals, two distinct NF-κB signaling pathways exist to respond to different stimuli. The classic pathway, mediated by the RelA:p50 dimer and stimulated by cytokines, including tumor necrosis factor-α (TNF-α) and infectious agents, is dependent on the degradation of IκBs. IKKβ is a major kinase component. It phosphorylates IκBs to trigger ubiquitin-based degradation, leading to the release of the RelA:p50 dimer. The alternative pathway mediated by the RelB:p52 dimer is dependent on IKKα-activated processing of p100 and release of p52. SN52 is a potent, competitive, and cell-permeable inhibitor of NF-κB.
SN52 inhibits DMXAA-induced nuclear translocation of RelB in BMDCs. It selectively blocks the alternative pathway by competing with p52 for nuclear import proteins, and it does not change the activation of canonical NF-κB signaling. In addition, SN52 enhances radiosensitivity of prostate cancer cells. Furthermore, it has only minor toxic effect on normal prostate cells. In addition, it has no inhibitory effect on the classic pathway and Sp1 nuclear translocation, and SN52-based selective blockade of the alternative pathway has a limited effect on normal prostate cells.
In summary, SN52 is a potent, competitive, and cell-permeable inhibitor of NF-κB2. SN52 is also a variant of the SN50 peptide, and it inhibits the nuclear translocation of p52-RelB heterodimers. It also has a strong radiosensitization effect on prostate cancer cells. In a word, SN52 has the potential for the research of cancer.