title: Prenyltransferases regulate CD20 protein levels and influence anti-CD20 monoclonal antibody-mediated activation of complement-dependent cytotoxicity.
abstract: Anti-CD20 monoclonal antibodies (mAbs) are successfully used in the management of non-Hodgkin lymphomas and chronic lymphocytic leukemia. We have reported previously that statins induce conformational changes in CD20 molecules and impair rituximab-mediated complement-dependent cytotoxicity. Here we investigated in more detail the influence of farnesyltransferase inhibitors (FTIs) on CD20 expression and antitumor activity of anti-CD20 mAbs. Among all FTIs studied, L-744,832 had the most significant influence on CD20 levels. It significantly increased rituximab-mediated complement-dependent cytotoxicity against primary tumor cells isolated from patients with non-Hodgkin lymphomas or chronic lymphocytic leukemia and increased CD20 expression in the majority of primary lymphoma/leukemia cells. Incubation of Raji cells with L-744,832 led to up-regulation of CD20 at mRNA and protein levels. Chromatin immunoprecipitation assay revealed that inhibition of farnesyltransferase activity was associated with increased binding of PU.1 and Oct-2 to the CD20 promoter sequences. These studies indicate that CD20 expression can be modulated by FTIs. The combination of FTIs with anti-CD20 mAbs is a promising therapeutic approach, and its efficacy should be examined in patients with B-cell tumors.
authors: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors: Magdalena
authors: M
authors: Winiarska
authors: Dominika
authors: D
authors: Nowis
authors: Jacek
authors: J
authors: Bil
authors: Eliza
authors: E
authors: Glodkowska-Mrowka
authors: Angelika
authors: A
authors: Muchowicz
authors: Malgorzata
authors: M
authors: Wanczyk
authors: Kamil
authors: K
authors: Bojarczuk
authors: Michal
authors: M
authors: Dwojak
authors: Malgorzata
authors: M
authors: Firczuk
authors: Ewa
authors: E
authors: Wilczek
authors: Malgorzata
authors: M
authors: Wachowska
authors: Katarzyna
authors: K
authors: Roszczenko
authors: Marta
authors: M
authors: Miaczynska
authors: Justyna
authors: J
authors: Chlebowska
authors: Grzegorz Wladyslaw
authors: GW
authors: Basak
authors: Jakub
authors: J
authors: Golab
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D018951:Antigens, CD20 / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003165:Complement System Proteins / Q000737:chemistry*; D004122:Dimethylallyltranstransferase / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005434:Flow Cytometry / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D004791:Enzyme Inhibitors; C096898:L 744832; D003165:Complement System Proteins; D008715:Methionine; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase