title: Highly efficient, in-vivo Fas-mediated apoptosis of B-cell lymphoma by hexameric CTLA4-FasL.
abstract: Non-Hodgkin lymphomas (NHLs) account for 4% of all malignancies. 5-year survival rate increased to 50% with new treatment modalities, however there is need for new effective treatment for the more aggressive, relapsing forms. Recently, CTLA4-FasL, that can bind to B7 and Fas receptor (Fas), was shown to induce robust apoptosis of cell lines originating from B cell lymphomas expressing both B7 and Fas, by activating pro-apoptotic signals in parallel to abrogating anti-apoptotic ones. The present study focuses on the unique properties of CTLA4-FasL as a potent apoptosis inducer of malignant cells in-vitro and in a xenograft model. CTLA4-FasL was found to naturally form a stable homo-hexamer. CTLA4-FasL induces robust apoptosis of a large variety of malignant cells while relatively sparing non-malignant ones, being more efficient when both receptors (B7 and Fas) are expressed on target cells. Even in non-B7 expressing cells, CTLA4-FasL exhibited better apoptotic activity than its parts, alone or in combination, however, only in B7 expressing cells apoptosis occurs at low concentrations and CTLA4-FasL induces activation of apoptotic signals and reduces anti-apoptotic ones. Importantly, CTLA4-FasL efficiently inhibited the growth of human B cell lineage tumors in a xenograft model, by provoking tumor cells' apoptosis. Thus, CTLA4-FasL, a natural homo-hexamer protein, induces robust apoptosis of malignant cells, in-vitro and in-vivo. In B-cell lymphoma, its potency stems from the combination of its synergistic effect of activating the caspases while abrogating the anti-apoptotic signaling, with its unique hexameric structure, making CTLA4-FasL a promising candidate for aggressive B cell lymphomas treatment.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aronin
authors.forename: Shira
authors.initials: S
authors.lastname: Amsili
authors.forename: Tatyana B
authors.initials: TB
authors.lastname: Prigozhina
authors.forename: Kobi
authors.initials: K
authors.lastname: Tzdaka
authors.forename: Roy
authors.initials: R
authors.lastname: Shen
authors.forename: Leonid
authors.initials: L
authors.lastname: Grinmann
authors.forename: Fanny
authors.initials: F
authors.lastname: Szafer
authors.forename: Per
authors.initials: P
authors.lastname: Edebrink
authors.forename: Mari-Anne
authors.initials: MA
authors.lastname: Rauvola
authors.forename: Noam
authors.initials: N
authors.lastname: Shani
authors.forename: Michal Dranitzki
authors.initials: MD
authors.lastname: Elhalel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D060908:CTLA-4 Antigen / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007525:Isoelectric Focusing; D016393:Lymphoma, B-Cell / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D003432:Cross-Linking Reagents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D011993:Recombinant Fusion Proteins; D019014:fas Receptor