title: Selective killing of Burkitt's lymphoma cells by mBAFF-targeted delivery of PinX1.
abstract: Increased expression of BAFF (B cell-activating factor belonging to the TNF family) and its receptors has been identified in numerous B-cell malignancies. A soluble human BAFF mutant (mBAFF), binding to BAFF receptors but failing to activate B-lymphocyte proliferation, may function as a competitive inhibitor of BAFF and may serve as a novel ligand for targeted therapy of BAFF receptor-positive malignancies. Pin2/TRF1-interacting protein X1 (PinX1), a nucleolar protein, potently inhibits telomerase activity and affects tumorigenicity. In this study, we generated novel recombinant proteins containing mBAFF, a polyarginine tract 9R and PinX1 (or its C/N terminal), to target lymphoma cells. The fusion proteins PinX1/C-G(4)S-9R-G(4)S-mBAFF and PinX1/C-9R-mBAFF specifically bind and internalize into BAFF receptor-positive cells, and subsequently induce growth inhibition and apoptosis. The selective cytotoxicity of the fusion proteins is a BAFF receptor-mediated process and depends on mBAFF, PinX1/C and 9R. Moreover, the fusion proteins specifically kill BAFF receptor-expressing Burkitt's lymphoma (BL) cells by inhibiting telomerase activity and the consequent shortening of telomeres. Therapeutic experiments using PinX1C-G(4)S-9R-G(4)S-mBAFF in severe combined immunodeficient (SCID) mice implanted with Raji cells showed significantly prolonged survival times, indicating the in vivo antitumor activity of the fusion protein. These results suggest the potential of PinX1/C-G(4)S-9R-G(4)S-mBAFF in targeted therapy of BL.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Gao
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Yan
authors.forename: F
authors.initials: F
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001667:Binding, Competitive; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D050505:Mutant Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015996:Survival Rate; D019098:Telomerase / Q000037:antagonists & inhibitors; D025521:Tumor Suppressor Proteins / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D018797:Cell Cycle Proteins; D050505:Mutant Proteins; C440808:PINX1 protein, human; D011993:Recombinant Fusion Proteins; C505719:TNFSF13B protein, human; D025521:Tumor Suppressor Proteins; D019098:Telomerase