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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3044-3052
Role of NF- B in the Rescue of Multiple Myeloma Cells From
Glucocorticoid-Induced Apoptosis by Bcl-2
Rena Feinman,
Jadd Koury,
Michael Thames,
Bart Barlogie,
Joshua Epstein, and
David S. Siegel
From Myeloma and Transplantation Research Center, Arkansas Cancer
Research Center, University of Arkansas for Medical Sciences, Little
Rock, AR.
The molecular mechanisms by which multiple myeloma (MM) cells evade
glucocorticoid-induced apoptosis have not been delineated. Using a
human IgA MM cell line (ARP-1), we found that dexamethasone (Dex)-induced apoptosis is associated with decreased NF-B DNA binding and B-dependent transcription. Both nuclear p50:p50 and p50:p65 NF-B complexes are detected in ARP-1 cells by supershift electrophoretic mobility shift assay (EMSA). Dex-mediated inhibition of
NF-B DNA binding precedes a notable increase in annexin
V binding, thereby indicating that diminished NF-B activity is an
early event in Dex-induced apoptosis. Overexpression of bcl-2 in ARP-1
cells prevents Dex-mediated repression of NF-B activity and
apoptosis. Sustained NF-B 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 IB
proteins. In addition, enforced bcl-2 expression in ARP-1 cells did not
prevent the augmentation of IB protein by Dex. We also noted a
possible association between Dex-mediated downregulation of NF-B 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-B activation-signaling pathway and the potential
use of NF-B as a biomarker in progressive MM.
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