Published in:
Blood, 109 (2007) 9, Seite 3982-3988
Language:
English
DOI:
10.1182/blood-2006-10-053959
ISSN:
0006-4971;
1528-0020
Origination:
Footnote:
Description:
AbstractThe proteasome inhibitor bortezomib has been shown to possess promising antitumor activity and significant efficacy against a variety of malignancies. Different studies demonstrated that bortezomib breaks the chemoresistance in different tumor cells basically by altering nuclear factor–κB (NF-κB) activity. NF-κB has been shown to be constitutively active in most primary Hodgkin-Reed-Sternberg (H-RS) cells in lymph node sections and in Hodgkin lymphoma (HL) cell lines and was suggested to be a central molecular switch in apoptosis resistance in HL. Here we report a bimodal effect of bortezomib in HL cells. Whereas high-dose bortezomib induced direct cytotoxicity that correlated with decreased NF-κB activity, low-dose bortezomib sensitized HL cells against a variety of cytotoxic drugs without altering NF-κB action. Strikingly, bortezomib induced marked XIAP down-regulation at the posttranslational level that was independent of the NF-κB status. Similarly, RNA interference (RNAi)–mediated XIAP down-regulation generated susceptibility to cytostatic agents. The results identify XIAP as an NF-κB–independent target of bortezomib action that controls the chemoresistant phenotype of HL cells.