E3 泛素连接酶 HOIP 减弱顺铂诱导的细胞凋亡。,Cancer Research

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E3 泛素连接酶 HOIP 减弱顺铂诱导的细胞凋亡。
Cancer Research ( IF 12.5 ) Pub Date : 2014 Apr 15 , DOI: 10.1158/0008-5472.can-13-2131
Craig MacKay ₁ , Eilís Carroll ₁ , Adel F M Ibrahim ₁ , Amit Garg ₁ , Gareth J Inman ₂ , Ronald T Hay ₃ , Arno F Alpi ₁

Affiliation

基因毒素顺铂常用于化疗治疗实体瘤，但我们对药物反应机制的了解有限。在重点 siRNA 筛选中，使用靶向泛素和泛素样信号传导基因的 siRNA 文库，我们将 E3 泛素连接酶 HOIP 鉴定为顺铂诱导的基因毒性的关键调节剂。HOIP 与 SHARPIN 和 HOIL-1L 形成线性泛素组装复合物 (LUBAC)。我们表明缺乏 HOIP 连接酶复合物的细胞对顺铂表现出超敏反应。这是由于 caspase-8/caspase-3 介导的细胞凋亡急剧增加，这种细胞凋亡严格依赖于 ATM 而非 ATR 介导的 DNA 损伤检查点激活。此外，应激反应激酶 JNK 的基础和顺铂诱导的活性在 HOIP 耗尽的细胞中得到增强，相反，JNK 抑制可以增加细胞对顺铂的抵抗力并逆转 HOIP 耗尽细胞中的凋亡过度激活。此外，我们表明 HOIP 消耗通过增强的凋亡细胞死亡反应使源自各种来源的癌症的癌细胞变得敏感。我们还提供证据表明，归类为顺铂耐药的卵巢癌细胞可以在 HOIP 下调后恢复敏感性。累积起来，我们的研究确定了 HOIP 调节的抗细胞凋亡信号通路，我们将 HOIP 视为开发组合化学疗法以增强铂类抗癌药物疗效的潜在目标。来自各种起源的癌，通过增强的凋亡细胞死亡反应。我们还提供证据表明，归类为顺铂耐药的卵巢癌细胞可以在 HOIP 下调后恢复敏感性。累积起来，我们的研究确定了 HOIP 调节的抗细胞凋亡信号通路，我们将 HOIP 视为开发组合化学疗法以增强铂类抗癌药物疗效的潜在目标。来自各种起源的癌，通过增强的凋亡细胞死亡反应。我们还提供证据表明，归类为顺铂耐药的卵巢癌细胞可以在 HOIP 下调后恢复敏感性。累积起来，我们的研究确定了 HOIP 调节的抗细胞凋亡信号通路，我们将 HOIP 视为开发组合化学疗法以增强铂类抗癌药物疗效的潜在目标。

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E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin.

The genotoxin cisplatin is commonly used in chemotherapy to treat solid tumors, yet our understanding of the mechanism underlying the drug response is limited. In a focused siRNA screen, using an siRNA library targeting genes involved in ubiquitin and ubiquitin-like signaling, we identified the E3 ubiquitin ligase HOIP as a key regulator of cisplatin-induced genotoxicity. HOIP forms, with SHARPIN and HOIL-1L, the linear ubiquitin assembly complex (LUBAC). We show that cells deficient in the HOIP ligase complex exhibit hypersensitivity to cisplatin. This is due to a dramatic increase in caspase-8/caspase-3-mediated apoptosis that is strictly dependent on ATM-, but not ATR-mediated DNA damage checkpoint activation. Moreover, basal and cisplatin-induced activity of the stress response kinase JNK is enhanced in HOIP-depleted cells and, conversely, JNK inhibition can increase cellular resistance to cisplatin and reverse the apoptotic hyperactivation in HOIP-depleted cells. Furthermore, we show that HOIP depletion sensitizes cancer cells, derived from carcinomas of various origins, through an enhanced apoptotic cell death response. We also provide evidence that ovarian cancer cells classified as cisplatin-resistant can regain sensitivity following HOIP downregulation. Cumulatively, our study identifies a HOIP-regulated antiapoptotic signaling pathway, and we envisage HOIP as a potential target for the development of combinatorial chemotherapies to potentiate the efficacy of platinum-based anticancer drugs.

更新日期：2017-01-31

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