title: RelA, p50 and inhibitor of kappa B alpha are elevated in human metastatic melanoma cells and respond aberrantly to ultraviolet light B.
abstract: Metastatic melanomas are typically resistant to radiation and chemotherapy. The underlying basis for this phenomenon may result in part from defects in apoptotic pathways. Nuclear factor kappa B (NFkappaB) has been shown to control apoptosis in many cell types and normally functions as an immediate stress response mechanism that is rigorously controlled by multiple inhibitory complexes. We have previously shown that NFkappaB binding is elevated in metastatic melanoma cells relative to normal melanocytes. In the current study, Western blot analysis showed that, compared with normal melanocytes, melanoma cell lines have higher nuclear levels of the NFkappaB subunits p50 (7-fold) and RelA (5-10-fold). In response to tumor necrosis factor-alpha (TNFalpha), both melanocytes and melanoma cells showed increased nuclear p50 and RelA levels, but levels in melanoma cells remained higher than in melanocytes. We also found that melanoma cells expressed higher cytoplasmic levels of RelA, p105/p50 and the inhibitory protein, inhibitor of kappa B alpha (IkappaBalpha) than melanocytes. To directly test whether RelA expression has an impact on melanoma cell survival, we used antisense RelA phosphorothioate oligonucleotides and found that melanoma cell viability was significantly decreased compared with untreated or control cultures. The constitutive activation of NFkappaB in metastatic melanoma cell cultures may, therefore, support an inappropriate cell survival pathway that can be therapeutically manipulated.
authors.affiliation: Department of Medicine and Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange 92868, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: McNulty
authors.forename: N B
authors.initials: NB
authors.lastname: Tohidian
authors.forename: F L
authors.initials: FL
authors.lastname: Meyskens
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D020672:I-kappa B Proteins; D007231:Infant, Newborn; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D052002:NF-kappa B p50 Subunit; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000503:physiopathology* / Q000532:radiotherapy; D012333:RNA, Messenger / Q000378:metabolism / Q000528:radiation effects; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha