Selective inhibition of PED protein expression sensitizes B-cell chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis
Selective inhibition of PED protein expression sensitizes B-cell chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis
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DOI：
10.1002/ijc.22495
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发表时间：
2007-03-15
影响因子：
6.4
通讯作者：
Condorelli, Gerolama
中科院分区：
文献类型：
--
作者：
Garofalo, Michela;Romano, Giulia;Condorelli, Gerolama
b细胞慢性淋巴细胞白血病（B-CLL）细胞不能进行凋亡。这种抵抗细胞死亡的机制在很大程度上仍然是未知的。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）能有效杀死肿瘤细胞，但不能杀死正常细胞，因此是治疗癌症的一种有吸引力的工具。不幸的是，来自B-CLL患者的淋巴细胞对trail介导的细胞凋亡具有耐药性。因此，我们旨在研究具有广泛抗凋亡作用的ed家族成员PED在这种耐药中的作用。我们证明从B- cll患者获得的B淋巴细胞表达高水平的PED。用特异性PED反义寡核苷酸（一种蛋白质合成抑制剂或HDAC抑制剂）处理B-CLL细胞，诱导PED显著下调，并使这些细胞对trail诱导的细胞死亡敏感。这些发现表明，PED直接参与了对trail诱导的B-CLL细胞凋亡的抵抗。它还确定了这种ed家族成员作为这种白血病的潜在治疗靶点。(c) 2006 Wiley-Liss, Inc。
B-cell chronic lymphocytic leukaemia (B-CLL) cells fail to undergo apoptosis. The mechanism underlying this resistance to cell death is still largely unknown. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells, and thus represents an attractive tool for the treatment of cancer. Unfortunately, lymphocytes from B-CLL patients are resistant to TRAIL-mediated apoptosis. Thus, we aimed to study the involvement of PED, a DED-family member with a broad antiapoptotic action, in this resistance. We demonstrate that B lymphocytes obtained from patients with B-CLL express high levels of PED. Treatment of B-CLL cells with specific PED antisense oligonucleotides, a protein synthesis inhibitor or HDAC inhibitors, induced a significant downregulation of PED and sensitized these cells to TRAIL-induced cell death. These findings suggest a direct involvement of PED in resistance to TRAIL-induced apoptosis in B-CLL. It also identifies this DED-family member as a potential therapeutic target for this form of leukaemia. (c) 2006 Wiley-Liss, Inc.