Targeting cannabinoid receptors to treat leukemia:: Role of cross-talk between extrinsic and intrinsic pathways in Δ9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells
Targeting cannabinoid receptors to treat leukemia:: Role of cross-talk between extrinsic and intrinsic pathways in Δ9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells
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DOI：
10.1016/j.leukres.2005.01.014
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发表时间：
2005-08-01
影响因子：
2.7
通讯作者：
Nagarkatti, PS
中科院分区：
文献类型：
--
作者：
Lombard, C;Nagarkatti, M;Nagarkatti, PS
靶向大麻素受体最近已被证明可以触发细胞凋亡，并提供了一种新的治疗模式，对免疫系统的恶性肿瘤。然而，这种癌症中细胞凋亡的确切机制以前尚未得到解决。在这项研究中，我们使用的人Jurkat白血病细胞系与缺陷的内在和外在的信号通路，以阐明的机制，Δ（9）-四氢大麻酚（THC）诱导的细胞凋亡。我们观察到FADD或caspase-8缺陷的Jurkat细胞对凋亡部分抵抗，而显性阴性caspase-9突变细胞对凋亡完全抵抗。半胱天冬酶抑制剂的使用证实了这些结果。此外，Bcl-2的过表达使细胞在早期时间点对THC具有抗性，但在长时间暴露后不具有抗性。THC处理导致野生型和FADD缺陷型Jurkat细胞中Δ psi（m）的损失，从而表明THC诱导的内在途径不依赖于FADD。野生型Jurkat细胞的THC处理引起细胞色素c释放，以及半胱天冬酶-8、-9、-2、-10和Bid的裂解。半胱天冬酶-2抑制剂阻断了野生型Jurkat细胞中THC诱导的半胱天冬酶-3，但没有Δ psi（m）的损失。总之，这些数据表明，内在途径在THC诱导的细胞凋亡中起着更关键的作用，而外在途径可能通过与内在途径的串扰促进细胞凋亡。(c)2005爱思唯尔有限公司保留所有权利。
Targeting cannabinoid receptors has recently been shown to trigger apoptosis and offers a novel treatment modality against malignancies of the immune system. However, the precise mechanism of apoptosis in such cancers has not been previously addressed. In this study, we used human Jurkat leukemia cell lines with defects in intrinsic and extrinsic signaling pathways to elucidate the mechanism of apoptosis induced by Delta(9)-tetrahydrocannabinol (THC). We observed that Jurkat cells deficient in FADD or caspase-8 were partially resistant to apoptosis, while dominant-negative caspase-9 mutant cells were completely resistant to apoptosis. Use of caspase inhibitors confirmed these results. Furthermore, overexpression of Bcl-2 rendered the cells resistant to THC at early time points but not upon prolonged exposure. THC treatment led to loss of Delta psi(m), in both wild-type and FADD-deficient Jurkat cells thereby suggesting that THC-induced intrinsic pathway was independent of FADD. THC treatment of wild-type Jurkat cells caused cytochrome c release, and cleavage of caspase-8, -9, -2, -10, and Bid. Caspase-2 inhibitor blocked THC-induced caspase-3 in wild-type Jurkat cells but not loss of Delta psi(m). Together, these data suggest that the intrinsic pathway plays a more critical role in THC-induced apoptosis while the extrinsic pathway may facilitate apoptosis via cross-talk with the intrinsic pathway. (c) 2005 Elsevier Ltd. All rights reserved.