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首页> 外文期刊>Journal of Cell Science >Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency
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Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency

机译：具有ATRX和PML缺乏的癌细胞中Cytolytic HSV-1的合成致死性

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Cancers that utilize the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of promyelocytic leukemia nuclear bodies (PML NBs) that are required for intrinsic immunity to various viruses. Here, we asked whether ATRX deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus.
机译：利用端粒剂（ALT）机制的癌症用于端粒维持的癌症往往难以治疗并具有差的预后差。它们也通常缺乏ATRX蛋白，ALT活性的阻遏物的表达，以及所需的基因粒细胞白血病核体（PML NBs）对各种病毒所需的一组分。在这里，我们询问ATRX缺乏是否在ALT癌细胞中产生了脆弱性，这可以用于治疗目的。我们在一系列细胞类型中显示出突变疱疹病毒类型1（HSV-1）缺乏ICP0，一种降解包括ATRX的PML NB成分的蛋白质在感染ATRX缺陷细胞中更有效地为1千倍。比野生型ATRX表达细胞。共培养的初级和亚型缺乏癌细胞的感染显示突变体HSV-1选择性地杀死的ATRX缺陷细胞。对突变体HSV-1感染的敏感性也与PML蛋白质水平同时相关，我们表明ATRX在转录和转录后水平上推动PML表达。这些数据基于ATRX或PML水平提供了预测的基础，该肿瘤将响应选择性的溶解疱疹病毒。

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