Sensitivity of adult T-cell leukaemia lymphoma cells to tumour necrosis factor-related apoptosis-inducing ligand
Sensitivity of adult T-cell leukaemia lymphoma cells to tumour necrosis factor-related apoptosis-inducing ligand
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DOI：
10.1111/j.1365-2141.2004.05289.x
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发表时间：
2005-01-01
影响因子：
6.5
通讯作者：
Kamihira, S
中科院分区：
文献类型：
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作者：
Hasegawa, H;Yamada, Y;Kamihira, S
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)可诱导许多转化细胞的凋亡，但不能诱导正常细胞的凋亡，因此TRAIL已成为一种新型的抗癌药物。成人T细胞白血病淋巴瘤(ATLL)是一种T淋巴细胞起源的肿瘤，病因学上与人类T淋巴细胞趋化病毒1型(HTLV-I)有关，对标准的抗癌治疗具有耐药性。因此，我们在这项研究中描述了ATLL细胞对TRAIL的敏感性。虽然大多数原代ATLL细胞和细胞系表面表达TRAIL死亡受体，但它们对TRAIL仅表现出有限的敏感性。在10个ATLL细胞系中，1个敏感，但2个死亡受体表达不足，2个耐药机制未知，死亡信号在caspase-8上游消失，其余5个细胞株分别显示X连锁的凋亡抑制因子和Bcl2/Bclxl抑制外在和内在途径中的信号减弱。此外，HTLV-I Tax表达水平与TRAIL耐药性显著相关。有趣的是，ATLL细胞本身在细胞表面表达TRAIL。TRAIL的结构性产生可能提供抗性，从而允许TRAIL耐药ATIL细胞的发展。因此，ATLL细胞对TRAIL的耐药机制被分配给多个因素，而不是由一个确定的单一因素来解释。
Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells, but not in normal cells, and hence TRAIL has recently emerged as a novel anti-cancer agent. Adult T-cell leukaemia lymphoma (ATLL) is a neoplasm of T-lymphocyte origin aetiologically associated with human T-lymphotropic virus type 1 (HTLV-I), and is resistant to standard anti-cancer therapy. We thus characterized the sensitivity of ATLL cells to TRAIL in this study. Although most primary ATLL cells and cell lines expressed TRAIL death receptors on their surface, they showed only restricted sensitivity to TRAIL. Among the 10 ATLL cell lines examined, one was sensitive, but two had insufficient death-receptor expression, two had an unknown resistant mechanism with abrogation of the death signal upstream of caspase-8, and the remaining five showed attenuation of the signal in both extrinsic and intrinsic pathways by X-linked inhibitor of apoptosis and Bcl-2/Bcl-xL respectively. Furthermore, the level of HTLV-I tax expression was significantly correlated to TRAIL resistance. Interestingly, ATLL cells themselves expressed TRAIL on the cell surface. Constitutive production of TRAIL may offer resistance, thus allowing the development of TRAIL-resistant ATLL cells. Consequently, the resistant mechanism in ATLL cells against TRAIL was assigned to multiple factors and was not explained by a definitive single agent.