NF-kappaB-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs.
The 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-kappaB (NF-kappaB) activity. NF-kappaB 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-kappaB activity, low-dose bortezomib sensitized HL cells against a variety of cytotoxic drugs without altering NF-kappaB action. Strikingly, bortezomib induced marked XIAP down-regulation at the posttranslational level that was independent of the NF-kappaB status. Similarly, RNA interference (RNAi)-mediated XIAP down-regulation generated susceptibility to cytostatic agents. The results identify XIAP as an NF-kappaB-independent target of bortezomib action that controls the chemoresistant phenotype of HL cells.
Kashkar
Hamid
H
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Köln, Germany. h.kashkar@uni-koeln.de
Deggerich
Anke
A
Seeger
Jens-Michael
JM
Yazdanpanah
Benjamin
B
Wiegmann
Katja
K
Haubert
Dirk
D
Pongratz
Carola
C
Krönke
Martin
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006689:Hodgkin Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology*; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis* / Q000235:genetics
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011719:Pyrazines; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000069286:Bortezomib