title: Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma.
abstract: Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma.
authors: Department of Respiratory Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors: Kai
authors: K
authors: Wang
authors: Yu
authors: Y
authors: Jiang
authors: Weiyan
authors: W
authors: Zheng
authors: Zhiyong
authors: Z
authors: Liu
authors: Hui
authors: H
authors: Li
authors: Jianzhou
authors: J
authors: Lou
authors: Meidi
authors: M
authors: Gu
authors: Xiaojian
authors: X
authors: Wang
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C518018:PE-binding protein 4, human; D049488:Phosphatidylethanolamine Binding Protein; D017382:Reactive Oxygen Species; D000069283:Rituximab