In:
Blood, American Society of Hematology, Vol. 110, No. 7 ( 2007-10-01), p. 2286-2295
Kurzfassung:
Salinosporamide A (also called NPI-0052), recently identified from the marine bacterium Salinispora tropica, is a potent inhibitor of 20S proteasome and exhibits therapeutic potential against a wide variety of tumors through a poorly understood mechanism. Here we demonstrate that salinosporamide A potentiated the apoptosis induced by tumor necrosis factor α (TNF), bortezomib, and thalidomide, and this correlated with down-regulation of gene products that mediate cell proliferation (cyclin D1, cyclooxygenase-2 [COX-2], and c-Myc), cell survival (Bcl-2, Bcl-xL, cFLIP, TRAF1, IAP1, IAP2, and survivin), invasion (matrix metallopro-teinase-9 [MMP-9] and ICAM-1), and angiogenesis (vascular endothelial growth factor [VEGF]). Salinosporamide A also suppressed TNF-induced tumor cell invasion and receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis. We also found that it suppresse d both constitutive and inducible NF-κB activation. Compared with bortezomib, MG-132, N-acetyl-leucyl-leucyl-norleucinal (ALLN), and lactacystin, salinosporamide A was found to be the most potent suppressor of NF-κB activation. Further studies showed that salinosporamide A inhibited TNF-induced inhibitory subunit of NF-κB α (IκBα) degradation, nuclear translocation of p65, and NF-κB-dependent reporter gene expression but had no effect on IκBα kinase activation, IκBα phosphorylation, or IκBα ubiquitination. Thus, overall, our results indicate that salinosporamide A enhances apoptosis, suppresses osteoclastogenesis, and inhibits invasion through suppression of the NF-κB pathway.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2007-04-084996
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2007
ZDB Id:
1468538-3
ZDB Id:
80069-7
