Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells.
Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells.
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DOI：
10.1038/cddis.2014.5
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发表时间：
2014-01-30
影响因子：
9
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肿瘤坏死因子相关的凋亡诱导配体(TRAIL/TNFSF10/Apo2L)可诱导多种肿瘤细胞的凋亡，而对正常肿瘤细胞的毒性可忽略不计，有望用于肿瘤治疗。然而，TRAIL也可以在抵抗该细胞因子诱导的凋亡的癌细胞中诱导增殖和迁移信号。在这一点上，TRAIL的肿瘤选择性和平衡凋亡与生存的分子机制在很大程度上仍然难以捉摸。我们在这里表明，编码尿激酶型纤溶酶原激活剂(UPA)的PLAU的高mRNA水平是具有功能TRAIL信号的癌细胞的特征。值得注意的是，uPA水平的降低使癌细胞对TRAIL敏感，导致明显的细胞凋亡增加。机制分析表明，在uPA缺失的细胞中发生了三个分子事件：基础ERK1/2生存信号减少，前配体诱骗受体2(DcR2)-死亡受体5(DR5)相互作用减少，TRAIL攻击时DcR2向死亡诱导信号复合体的募集减弱。伴随这些现象的是FADD和proaspase-8募集和加工的增加，从而引导细胞走向caspase依赖的细胞死亡，这种死亡在很大程度上独立于内在的凋亡途径。总而言之，我们的结果揭示了PLAU mRNA水平作为识别TRAIL反应的肿瘤细胞的标志，并强调了uPA信号在TRAIL挑战时“凋亡与生存”决策过程中的关键作用。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10/Apo2L) holds promise for cancer therapy as it induces apoptosis in a large variety of cancer cells while exerting negligible toxicity in normal ones. However, TRAIL can also induce proliferative and migratory signaling in cancer cells resistant to apoptosis induced by this cytokine. In that regard, the molecular mechanisms underlying the tumor selectivity of TRAIL and those balancing apoptosis versus survival remain largely elusive. We show here that high mRNA levels of PLAU, which encodes urokinase plasminogen activator (uPA), are characteristic of cancer cells with functional TRAIL signaling. Notably, decreasing uPA levels sensitized cancer cells to TRAIL, leading to markedly increased apoptosis. Mechanistic analyses revealed three molecular events taking place in uPA-depleted cells: reduced basal ERK1/2 prosurvival signaling, decreased preligand decoy receptor 2 (DcR2)-death receptor 5 (DR5) interaction and attenuated recruitment of DcR2 to the death-inducing signaling complex upon TRAIL challenge. These phenomena were accompanied by increased FADD and procaspase-8 recruitment and processing, thus guiding cells toward a caspase-dependent cell death that is largely independent of the intrinsic apoptosis pathway. Collectively, our results unveil PLAU mRNA levels as marker for the identification of TRAIL-responsive tumor cells and highlight a key role of uPA signaling in ‘apoptosis versus survival' decision-making processes upon TRAIL challenge.