XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
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XRN1 缺失会在干扰素激活的癌细胞中诱导 PKR 依赖性细胞致死。
DOI：
10.1101/2023.08.01.551488
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Meyerson,Matthew
中科院分区：
文献类型：
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作者：
Zou,Tao;Zhou,Meng;Gupta,Akansha;Zhuang,Patrick;Fishbein,AlyssaR;Wei,HopeY;Zhang,Zhouwei;Cherniack,AndrewD;Meyerson,Matthew
新出现的数据表明，通过激活癌细胞中的双链RNA（dsRNA）传感器诱导病毒模拟反应是一种有前途的治疗策略。诱导病毒模拟的一种方法是靶向dsRNA传感途径的分子调节剂。在此，我们发现，在干扰素刺激基因高表达的癌细胞中，核糖核酸外切酶XRN 1是双链RNA传感器蛋白激酶R（PKR）的负调控因子，XRN 1缺失导致PKR通路激活，从而导致癌细胞死亡。JAK 1/2抑制剂ruxolitinib阻断干扰素信号传导可降低细胞PKR水平并挽救对XRN 1缺失的敏感性。相反，干扰素-β刺激可增加PKR水平并诱导对XRN 1失活的敏感性。最后，XRN 1缺失导致内源性互补正义/反义RNA的积累，这可能代表候选PKR配体。我们的数据展示了XRN 1如何调节PKR，以及这种相互作用如何在具有激活的干扰素细胞状态的癌细胞中产生脆弱性。
Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene expression.XRN1deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity toXRN1deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity toXRN1inactivation. Lastly,XRN1deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state.