Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5'UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

中文翻译：

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ISG15通过hnRNPA2B1的ISGylation抑制ABCC2的翻译，并增强顺铂耐药性卵巢癌细胞的药物敏感性。

长期以来，基于顺铂的化学疗法一直被认为是卵巢癌的标准化学疗法。但是，顺铂耐药性限制了卵巢癌患者的有益治疗。泛素样蛋白干扰素刺激基因15（ISG15）编码一个15 kDa的蛋白，与多种蛋白的翻译后修饰有关。在这项工作中，我们发现ISG15在卵巢癌的顺铂耐药组织和细胞系中下调。功能研究表明，野生型（WT）ISG15的过表达，但非ISGylatable（Mut）ISG15的过表达增加了抗性卵巢癌细胞对顺铂的细胞反应。此外，我们发现WT ISG15在蛋白质水平上降低了ABCC2表达。重要的是，ABCC2的过表达阻止了ISG15对顺铂的敏化作用。此外，我们确定hnRNPA2B1被募集到ABCC2 mRNA的5'UTR并促进了其翻译，这被ISG15阻断。我们进一步证明hnRNPA2B1可以被ISGylated，并且ISGylation阻止其募集到ABCC2 mRNA，从而抑制ABCC2的翻译。总之，我们针对ISG15的数据支持可能是顺铂耐药卵巢癌患者的潜在治疗策略。