OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug
OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug
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DOI：
10.1073/pnas.1815071116
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发表时间：
2019-03-12
影响因子：
11.1
通讯作者：
Silverman, Robert H.
中科院分区：
文献类型：
--
作者：
Banerjee, Shuvojit;Gusho, Elona;Silverman, Robert H.
逆转表观遗传沉默的药物，例如 DNA 甲基转移酶抑制剂 (DNMTi) 5-氮杂胞苷 (AZA)，对转录和肿瘤细胞存活具有深远影响。 AZA 是一种批准用于治疗骨髓增生异常综合征和急性髓性白血病的药物，并且正在针对不同的实体恶性肿瘤进行研究。 AZA 处理产生自体双链 RNA (dsRNA)，由低甲基化重复元件转录而成。 DNMTi 处理的细胞中自身 dsRNA 的积累导致 I 型 IFN 的产生和 IFN 刺激的基因表达。在这里，我们报道了 AZA 治疗引起的细胞死亡是通过 2', 5'-寡腺苷酸合成酶 (OAS)-RNase L 途径发生的。 OAS 是 IFN 诱导的酶，可响应 dsRNA 合成 RNase L 激活剂 2-5A。缺乏 RNase L 或 OAS1 至 3 的细胞对 AZA 高度耐药，用 RNase L 小分子抑制剂处理的野生型细胞也是如此。c-Jun NH2 末端激酶 (JNK) 的小分子抑制剂也能拮抗 AZA 响应的 RNase L 依赖性细胞死亡，这与 JNK 在 RNase L 诱导的细胞死亡中的作用一致 细胞凋亡。相反，转染 2-5A、ADAR1（编辑 dsRNA 并使其不稳定）、PDE12 或 AKAP7（降解 2-5A）缺陷或电离辐射（诱导 IFN 依赖性信号传导）的缺陷会增加 AZA 诱导的和 RNase L 依赖性细胞死亡的发生率。最后，OAS1 表达与 NCI-60 组肿瘤细胞系中的 AZA 敏感性相关，表明 OAS1 的水平可以作为预测肿瘤细胞 AZA 敏感性的生物标志物。这些研究最终可能会产生调节 AZA 及相关药物的抗肿瘤活性和毒性的药理学策略。
Drugs that reverse epigenetic silencing, such as the DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (AZA), have profound effects on transcription and tumor cell survival. AZA is an approved drug for myelodysplastic syndromes and acute myeloid leukemia, and is under investigation for different solid malignant tumors. AZA treatment generates self, double-stranded RNA (dsRNA), transcribed from hypomethylated repetitive elements. Self dsRNA accumulation in DNMTi-treated cells leads to type I IFN production and IFN-stimulated gene expression. Here we report that cell death in response to AZA treatment occurs through the 2', 5'-oligoadenylate synthetase (OAS)-RNase L pathway. OASs are IFN-induced enzymes that synthesize the RNase L activator 2-5A in response to dsRNA. Cells deficient in RNase L or OAS1 to 3 are highly resistant to AZA, as are wild-type cells treated with a small-molecule inhibitor of RNase L. A small-molecule inhibitor of c-Jun NH2-terminal kinases (JNKs) also antagonizes RNase L-dependent cell death in response to AZA, consistent with a role for JNK in RNase L-induced apoptosis. In contrast, the rates of AZA-induced and RNase L-dependent cell death were increased by transfection of 2-5A, by deficiencies in ADAR1 (which edits and destabilizes dsRNA), PDE12 or AKAP7 (which degrade 2-5A), or by ionizing radiation (which induces IFN-dependent signaling). Finally, OAS1 expression correlates with AZA sensitivity in the NCI-60 set of tumor cell lines, suggesting that the level of OAS1 can be a biomarker for predicting AZA sensitivity of tumor cells. These studies may eventually lead to pharmacologic strategies for regulating the antitumor activity and toxicity of AZA and related drugs.