title: NF-kappaB-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs.
abstract: 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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Köln, Germany. h.kashkar@uni-koeln.de
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.forename: Anke
authors.initials: A
authors.lastname: Deggerich
authors.forename: Jens-Michael
authors.initials: JM
authors.lastname: Seeger
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yazdanpanah
authors.forename: Katja
authors.initials: K
authors.lastname: Wiegmann
authors.forename: Dirk
authors.initials: D
authors.lastname: Haubert
authors.forename: Carola
authors.initials: C
authors.lastname: Pongratz
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
mesh_terms: 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
chemical_list: 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