Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2.
The molecular mechanisms by which multiple myeloma (MM) cells evade glucocorticoid-induced apoptosis have not been delineated. Using a human IgAkappa MM cell line (ARP-1), we found that dexamethasone (Dex)-induced apoptosis is associated with decreased NF-kappaB DNA binding and kappaB-dependent transcription. Both nuclear p50:p50 and p50:p65 NF-kappaB complexes are detected in ARP-1 cells by supershift electrophoretic mobility shift assay (EMSA). Dex-mediated inhibition of NF-kappaB DNA binding precedes a notable increase in annexin V binding, thereby indicating that diminished NF-kappaB activity is an early event in Dex-induced apoptosis. Overexpression of bcl-2 in ARP-1 cells prevents Dex-mediated repression of NF-kappaB activity and apoptosis. Sustained NF-kappaB DNA binding is also observed in two previously characterized Dex-resistant MM cell lines (RPMI8226 and ARH-77) that express moderate levels of endogenous bcl-2 and IkappaBalpha proteins. In addition, enforced bcl-2 expression in ARP-1 cells did not prevent the augmentation of IkappaBalpha protein by Dex. We also noted a possible association between Dex-mediated downregulation of NF-kappaB in freshly obtained primary myeloma cells and the patients' responsiveness to glucocorticoid-based chemotherapy. Collectively, our data suggest that the protective effects of bcl-2 in MM cells act upstream in the NF-kappaB activation-signaling pathway and the potential use of NF-kappaB as a biomarker in progressive MM.
Feinman
R
R
Myeloma and Transplantation Research Center, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Koury
J
J
Thames
M
M
Barlogie
B
B
Epstein
J
J
Siegel
D S
DS
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001853:Bone Marrow / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D019254:Genes, bcl-2; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D005938:Glucocorticoids; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone; D008156:Luciferases