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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3982-3988.
Prepublished online as a Blood First Edition Paper on December 21, 2006; DOI 10.1182/blood-2006-10-053959.
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NEOPLASIA
NF- B–independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs
Hamid Kashkar1,2,
Anke Deggerich1,
Jens-Michael Seeger1,
Benjamin Yazdanpanah1,
Katja Wiegmann1,
Dirk Haubert1,
Carola Pongratz1, and
Martin Krönke1,2
1 Institute for Medical Microbiology, Immunology and Hygiene and
2 the Center for Molecular Medicine Cologne, University of Cologne, Germany
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– B (NF-B) activity. NF-B 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-B activity, low-dose bortezomib sensitized HL cells against a variety of cytotoxic drugs without altering NF-B action. Strikingly, bortezomib induced marked XIAP down-regulation at the posttranslational level that was independent of the NF-B status. Similarly, RNA interference (RNAi)–mediated XIAP down-regulation generated susceptibility to cytostatic agents. The results identify XIAP as an NF-B–independent target of bortezomib action that controls the chemoresistant phenotype of HL cells.
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