Enhanced Fas-associated death domain recruitment by histone deacetylase inhibitors is critical for the sensitization of chronic lymphocytic leukemia cells to TRAIL-induced apoptosis
Enhanced Fas-associated death domain recruitment by histone deacetylase inhibitors is critical for the sensitization of chronic lymphocytic leukemia cells to TRAIL-induced apoptosis
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DOI：
10.1158/1535-7163.mct-09-0451
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发表时间：
2009-11-01
影响因子：
5.7
通讯作者：
Cohen, Gerald M.
中科院分区：
文献类型：
--
作者：
Inoue, Satoshi;Harper, Nick;Cohen, Gerald M.
慢性淋巴细胞白血病（CLL）是一种以成熟淋巴细胞凋亡失败为特征的不治之症。CLL细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有固有的抗性。组蛋白去乙酰化酶抑制剂（HDACi）预处理可使CLL细胞主要通过TRAIL-R1对trail介导的凋亡敏感，为CLL和其他恶性肿瘤的治疗提供了一种新的途径。作为一种HDACi， Depsipeptide （romidepsin）不增强TRAIL与TRAIL- r1的结合、TRAIL- r1的聚集或TRAIL- r1的内化，但它增强了死亡诱导信号复合体中fas相关死亡结构域蛋白（FADD）向TRAIL- r1的募集。与蛋白激酶C （PKC）激活剂phorbol 12-肉豆蔻酸13-乙酸酯（PMA）共处理可显著抑制hdac介导的FADD募集增加和trail诱导的细胞凋亡敏化，而PKC抑制剂可逆转这两种作用。因此，FADD募集增强是HDACi介导CLL细胞对trail诱导的凋亡致敏的关键步骤，这一步骤受到HDACi和phorbol 12-肉豆蔻酸酯13-醋酸酯的不同影响。利用生物素化的TRAIL和链凝素标记的TRAIL，我们鉴定了几种新的TRAIL受体相互作用蛋白，包括PKC β、淋巴细胞特异性蛋白酶1、Lyn和Syk。这些分子可能在CLL细胞的TRAIL信号传导中起着尚未被认识到的作用，抑制一种或多种这些激酶/磷酸酶可能提供克服TRAIL抗性的新靶点。[j]；8 (11): 3088 - 97)
Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by failure of mature lymphocytes to undergo apoptosis. CLL cells are inherently resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Pretreatment with histone deacetylase inhibitors (HDACi) sensitizes CLL cells to TRAIL-mediated apoptosis primarily via TRAIL-R1 and offers a novel approach for the therapy of CLL and other malignancies. Depsipeptide (romidepsin), a HDACi, did not enhance TRAIL binding to TRAIL-R1, TRAIL-R1 aggregation, or internalization of TRAIL-R1, but it enhanced Fas-associated death domain protein (FADD) recruitment to TRAIL-R1 in the death-inducing signaling complex. Cotreatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, dramatically inhibited the HDACi-mediated increase in FADD recruitment and sensitization to TRAIL-induced apoptosis and both of these were reversed by PKC inhibitors. Thus, enhanced FADD recruitment is a critical step in HDACi-mediated sensitization of CLL cells to TRAIL-induced apoptosis and this step is differentially affected by HDACi and phorbol 12-myristate 13-acetate. Using biotinylated TRAIL and streptactin-tagged TRAIL, we have identified several novel TRAIL receptor interacting proteins, including PKC beta, lymphocyte-specific protease-1, Lyn, and Syk. These molecules may play an as yet unappreciated role in TRAIL signaling in CLL cells and inhibition of one or more of these kinases/phosphatases may provide a novel target to overcome TRAIL resistance. [Mol Cancer Ther 2009;8(11):3088-97]