Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition
Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition
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DOI：
10.1158/0008-5472.can-15-2380
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发表时间：
2016-04-15
期刊：
影响因子：
11.2
通讯作者：
Helleday, Thomas
中科院分区：
文献类型：
--
作者：
Brautigam, Lars;Pudelko, Linda;Helleday, Thomas
癌细胞通常处于氧化还原不平衡状态，这推动了它们的生长和存活。为了补偿由肿瘤氧化还原环境诱导的氧化应激，癌细胞上调特定的非致癌成瘾酶，如MTH 1（NUDT 1），其使氧化的核苷酸解毒。在这里，我们表明，增加氧化应激在非恶性细胞诱导其敏感的MTH 1抑制的影响，而降低氧化压力的癌细胞保护免受抑制。此外，我们纯化了斑马鱼MTH 1，并解决了MTH 1与其抑制剂结合的晶体结构，突出了斑马鱼作为研究MTH 1生物学的相关工具。在没有MTH 1活性的情况下，将8-oxo-dGTP和2-OH-dATP递送到斑马鱼胚胎是高毒性的。此外，在斑马鱼中化学或遗传模拟活化缺氧信号显示，通常在癌症中观察到并与预后不良相关的HIF 1 α反应的病理性上调使胚胎对MTH 1抑制敏感。使用转基因斑马鱼系，其中细胞的氧化还原状态可以在体内监测，我们检测到缺氧信号激活后氧化压力的增加。用抗氧化剂N-乙酰-L-半胱氨酸预处理保护具有激活的缺氧信号的胚胎免受MTH 1抑制，这表明异常的氧化还原环境可能导致致敏。总之，MTH 1抑制可以提供治疗以缺氧信号失调或氧化还原失衡为特征的癌症的一般方法。(C)2016年AACR。
Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1 alpha response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. (C) 2016 AACR.