Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP
Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP
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DOI：
10.1128/mcb.23.4.1278-1291.2003
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发表时间：
2003-02-01
影响因子：
5.3
通讯作者：
Eriksson, JE
中科院分区：
文献类型：
--
作者：
Hietakangas, V;Poukkula, M;Eriksson, JE
细胞凋亡阈值的调节在分化和完全发育的器官系统的稳态中是非常重要的。触发分化已被用作抑制细胞增殖和加速恶性细胞凋亡的策略，其中凋亡阈值通常特征性地升高。为了更好地理解分化介导的细胞凋亡调控的机制，我们研究了K562红白血病细胞红系分化过程中的死亡受体反应，K562红白血病细胞通常对肿瘤坏死因子（TNF）α、FasL和TRAIL诱导的细胞凋亡具有高度抗性。然而，在氯化血红素介导的红系细胞分化，K562细胞特异性地失去了他们的抵抗肿瘤坏死因子相关的凋亡诱导配体（TRAIL），有效地杀死分化的细胞独立的线粒体凋亡信号。伴随着敏感性的增加，c-FLIP剪接变体c-FLIPL和c-FLIPS的表达下调，导致死亡诱导信号复合物（DISC）中caspase 8募集和切割的改变。c-FLIPL和c-FLIPS的稳定过表达可使细胞免于TRAIL介导的凋亡，并对DISC募集的caspase 8具有同种型特异性作用。我们的研究结果表明，c-FLIPL和c-FLIPS有效地控制TRAIL的反应，无论是通过不同的监管功能，并进一步暗示，恶性细胞的分化状态决定了他们的敏感性死亡受体信号。
Regulation of the apoptotic threshold is of great importance in the homeostasis of both differentiating and fully developed organ systems. Triggering differentiation has been employed as a strategy to inhibit cell proliferation and accelerate apoptosis in malignant cells, in which the apoptotic threshold is often characteristically elevated. To better understand the mechanisms underlying differentiation-mediated regulation of apoptosis, we have studied death receptor responses during erythroid differentiation of K562 erythroleukemia cells, which normally are highly resistant to tumor necrosis factor (TNF) alpha-, FasL-, and TRAIL-induced apoptosis. However, upon hemin-mediated erythroid differentiation, K562 cells specifically lost their resistance to TNF-related apoptosis-inducing ligand (TRAIL), which efficiently killed the differentiating cells independently of mitochondrial apoptotic signaling. Concomitantly with the increased sensitivity, the expression of both c-FLIP splicing variants, c-FLIPL and c-FLIPS, was downregulated, resulting in an altered caspase 8 recruitment and cleavage in the death-inducing signaling complex (DISC). Stable overexpression of both c-FLIPL and c-FLIPS rescued the cells from TRAIL-mediated apoptosis with isoform-specific effects on DISC-recruited caspase 8. Our results show that c-FLIPL and c-FLIPS potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals.