Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma.
Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma.
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人磷脂酰乙醇胺结合蛋白 4 的沉默可增强利妥昔单抗诱导的 B 细胞淋巴瘤死亡和化疗增敏
DOI：
10.1371/journal.pone.0056829
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wang K;Jiang Y;Zheng W;Liu Z;Li H;Lou J;Gu M;Wang X
利妥昔单抗是单独或联合化疗治疗非霍奇金淋巴瘤（B-NHL）的一线药物。然而，30-40%的B-NHL患者在治疗后对利妥昔单抗无反应或耐药。人磷脂酰乙醇胺结合蛋白4 （hPEBP4）是PEBP家族的新成员，具有抗细胞凋亡的功能。在本研究中，我们发现hPEBP4在高达90%的b细胞淋巴瘤患者中表达，但在正常淋巴结中仅表达16.7%。有趣的是，在B-NHL细胞中，hPEBP4过表达抑制了利妥昔单抗介导的补体依赖性细胞毒性（R-CDC）和抗体依赖性细胞毒性（ADCC），而hPEBP4的下调增强了利妥昔单抗在体外和体内的治疗效果。此外，hPEBP4沉默使原发性b -急性淋巴细胞白血病（B-ALL）细胞对R-CDC敏感。在利妥昔单抗介导的补体依赖性细胞毒性过程中，hPEBP4以pe结合域依赖的方式被募集到细胞膜上，抑制R-CDC诱导的钙通量和活性氧（ROS）的产生。这些事件有助于减少R-CDC在b细胞淋巴瘤中引起的细胞死亡。同时，hPEBP4敲低通过调节Bcl-xl、Cycline E、p21waf/cip1和p53的表达以及caspase-3和caspase-9的激活，增强了利图昔单抗在b细胞淋巴瘤细胞中的化学增敏作用。考虑到hPEBP4赋予细胞对利妥昔单抗治疗的耐药性，并优先在淋巴瘤组织中表达，它可能是b细胞淋巴瘤辅助治疗的潜在有价值的靶点。
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, p21waf/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.
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