Selective TRAIL-triggered apoptosis due to overexpression of TRAIL death receptor 5 (DR5) in P-glycoprotein-bearing multidrug resistant CEM/VBL1000 human leukemia cells.
Selective TRAIL-triggered apoptosis due to overexpression of TRAIL death receptor 5 (DR5) in P-glycoprotein-bearing multidrug resistant CEM/VBL1000 human leukemia cells.
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发表时间：
2010
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通讯作者：
S. Park;Khadijeh Bijangi‐Vishehsaraei;A. Safa
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作者：
S. Park;Khadijeh Bijangi‐Vishehsaraei;A. Safa
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种诱导死亡的细胞因子，由于其对肿瘤细胞相对于正常细胞的高度选择性凋亡诱导作用，因此具有作为癌症治疗剂的巨大前景。我们的研究结果表明，TRAIL选择性地触发P-糖蛋白（P-gp，ABCB 1）和DR 5过表达的CEM/VBL 1000多药耐药白血病细胞系的凋亡，但不是在亲本CEM细胞。此外，TRAIL处理降低了这些细胞中的P-gp表达。TRAIL诱导的细胞凋亡的机制分析显示，TRAIL超敏性是由于在CEM/VBL 1000变体中MDR发展期间TRAIL受体DR 5在蛋白质和mRNA水平上的稳健上调。DR 5的上调与内质网应激调节因子C/EBP同源转录因子（CH 0 P/GADD 153）的表达水平无关。TRAIL触发的细胞凋亡与FADD表达增加、半胱天冬酶-3、-8、-9和-10活化以及线粒体释放细胞色素c相关。因此，外源性和内源性凋亡途径都参与了这一过程。这些发现首次揭示了TRAIL处理通过强烈上调DR 5选择性地导致P-gp过表达的CEM/VBL 1000细胞凋亡。此外，这种对TRAIL的超敏性及其对降低这些细胞中P-gp表达的作用对使用TRAIL根除MDR恶性细胞具有重要的临床意义。
The death-inducing cytokine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), holds enormous promise as a cancer therapeutic due to its highly selective apoptosis-inducing action on neoplastic versus normal cells. Our results revealed that TRAIL selectively triggered apoptosis in the P-glycoprotein (P-gp, ABCB1) and DR5 overexpressing CEM/VBL1000 multidrug resistant leukemia cell line, but not in the parental CEM cells. Moreover, TRAIL treatment reduced P-gp expression in these cells. Mechanistic analysis of TRAIL-induced apoptosis revealed that TRAIL hypersensitivity is due to robust upregulation of the TRAIL receptor DR5 at the protein and mRNA levels during development of MDR in the CEM/VBL1000 variant. DR5 upregulation was independent of the level of expression of endoplasmic reticulum stress regulator C/EBP homologous transcription factor (CH0P/GADD153). TRAIL-triggered apoptosis was associated with increased expression of FADD; activation of caspases-3, -8, -9, and -10; and cytochrome c release from mitochondria. Therefore, both the extrinsic and intrinsic apoptosis pathways are involved in this process. These findings for the first time reveal that TRAIL treatment selectively causes apoptosis in P-gp-overexpressing CEM/VBL1000 cells through strong upregulation of DR5. Moreover, this hypersensitivity to TRAIL and its effect on reducing P-gp expression in these cells hold significant clinical implications for using TRAIL to eradicate MDR malignant cells.