Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
J Cell Biochem. 2010 May;110(1):21-34. doi: 10.1002/jcb.22549.
Defects in apoptosis are observed in many cancer cell types and contribute in a relevant way to tumorigenesis. Apoptosis is a complex and well-regulated cell death program that plays a key role in the control of cell homeostasis, particularly at the level of the hematopoietic system. Apoptosis can be initiated through two different mechanisms involving either activation of the death receptors (extrinsic pathway) or activation of a mitochondrial apoptotic process (intrinsic pathway). Among the various death receptors a peculiar role is played by TNF-related apoptosis-inducing ligand (TRAIL)-receptors (TRAIL-Rs) and their ligand TRAIL. TRAIL recently received considerable interest for its potent anti-tumor killing activity, sparing normal cells. Here, we will review the expression and the abnormalities of TRAIL/TRAIL-R system in hematologic malignancies. The large majority of primary hematologic tumors are resistant to TRAIL-mediated apoptosis, basically due to the activation of anti-apoptotic signaling pathway (such as NF-kappaB), overexpression of anti-apoptotic proteins (such as FLIP, Bcl-2, XIAP) or expression of TRAIL decoy receptors or reduced TRAIL-R1/-R2 expression. Strategies have been developed to bypass this TRAIL resistance and are based on the combination of TRAIL with chemotherapy or radiotherapy, or with proteasome or histone deacetylase or NF-kappaB inhibitors. The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, XIAP, Bcl-2). Many of these combinatorial therapies hold promise for future developments in treatment of hematologic malignancies.
凋亡缺陷在许多癌细胞类型中都有观察到，并在肿瘤发生中起到重要作用。凋亡是一种复杂且受到良好调控的细胞死亡程序，在控制细胞动态平衡方面发挥着关键作用，尤其是在造血系统中。凋亡可以通过两种不同的机制启动，涉及死亡受体的激活（外在途径）或线粒体凋亡过程的激活（内在途径）。在各种死亡受体中，TNF 相关凋亡诱导配体（TRAIL）受体（TRAIL-Rs）及其配体 TRAIL 起着特殊的作用。TRAIL 因其对肿瘤细胞的强大杀伤活性，而对正常细胞无毒性，最近受到了广泛关注。在这里，我们将回顾 TRAIL/TRAIL-R 系统在血液恶性肿瘤中的表达和异常。绝大多数原发性血液肿瘤对 TRAIL 介导的凋亡具有抗性，这主要是由于抗凋亡信号通路的激活（如 NF-κB）、抗凋亡蛋白（如 FLIP、Bcl-2、XIAP）的过表达或 TRAIL 诱饵受体的表达或 TRAIL-R1/-R2 表达的降低。已经开发了一些策略来绕过这种 TRAIL 抵抗，这些策略基于 TRAIL 与化疗或放疗的联合，或与蛋白酶体或组蛋白去乙酰化酶或 NF-κB 抑制剂的联合。与 TRAIL 联合使用的药物要么增强 TRAIL-R1/-R2 的表达，要么降低抗凋亡蛋白（c-FLIP、XIAP、Bcl-2）的表达。这些联合治疗中的许多都有望在血液恶性肿瘤的治疗中得到进一步发展。
