Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes.
Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes.
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DOI：
10.1091/mbc.e12-10-0737
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发表时间：
2013-07
影响因子：
3.3
通讯作者：
Sorger PK
中科院分区：
文献类型：
--
作者：
Flusberg DA;Roux J;Spencer SL;Sorger PK
被 TRAIL 或 FasR 激动剂部分杀死后存活的细胞会进入伴随炎症表型的抵抗状态。这种状态是短暂的，会在几天内衰减，但可以通过定期 TRAIL 治疗来维持。这一发现对于外源性细胞死亡剂的最佳剂量策略具有影响。当人类细胞克隆群暴露于细胞凋亡诱导剂时，一些细胞死亡，另一些细胞存活。这种部分杀伤不是由突变引起的，而是由调节细胞凋亡的蛋白质水平和活性中预先存在的随机差异引起的。在这里，我们检查了在两种不同死亡受体激动剂（肿瘤坏死因子相关凋亡诱导配体（TRAIL）和抗 FasR 抗体）治疗后存活的细胞的特性。我们发现“幸存者”细胞对 1 天后施用的第二次配体剂量具有高度抵抗力。抗性是可逆的，在没有死亡配体的情况下培养几天后会重置。在死亡配体敏感性和基因表达谱方面，“重置”细胞与未接受药物的细胞相同。 TRAIL 幸存者对 FasR 激活剂具有交叉耐药性，反之亦然，并表现出 NF-κB 依赖性炎症表型。值得注意的是，当存在 caspase 抑制剂时，在不存在细胞死亡的情况下会诱导可逆抗性，并且通过定期接触配体可以维持 1 周或更长时间，而且也不会导致细胞死亡。因此，细胞状态的随机差异可能会对促死亡配体的敏感性和促炎表型的获得产生持续的影响。 TRAIL 暴露的周期性对于诱导相反的细胞凋亡和生存机制所发挥的重要作用对于最佳治疗剂和方案的设计具有重要意义。
Cells that survive fractional killing by TRAIL or FasR agonists enter a state of resistance accompanied by inflammatory phenotypes. This state is transient, decaying over the course of several days, but can be sustained by periodic TRAIL treatments. This finding has implications for optimal dosing strategies of extrinsic cell death agents. When clonal populations of human cells are exposed to apoptosis-inducing agents, some cells die and others survive. This fractional killing arises not from mutation but from preexisting, stochastic differences in the levels and activities of proteins regulating apoptosis. Here we examine the properties of cells that survive treatment with agonists of two distinct death receptors, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and anti-FasR antibodies. We find that “survivor” cells are highly resistant to a second ligand dose applied 1 d later. Resistance is reversible, resetting after several days of culture in the absence of death ligand. “Reset” cells appear identical to drug-naive cells with respect to death ligand sensitivity and gene expression profiles. TRAIL survivors are cross-resistant to activators of FasR and vice versa and exhibit an NF-κB–dependent inflammatory phenotype. Remarkably, reversible resistance is induced in the absence of cell death when caspase inhibitors are present and can be sustained for 1 wk or more, also without cell death, by periodic ligand exposure. Thus stochastic differences in cell state can have sustained consequences for sensitivity to prodeath ligands and acquisition of proinflammatory phenotypes. The important role played by periodicity in TRAIL exposure for induction of opposing apoptosis and survival mechanisms has implications for the design of optimal therapeutic agents and protocols.