Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival.
Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival.
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DOI：
10.1038/srep26521
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发表时间：
2016-05-23
影响因子：
4.6
通讯作者：
Osada H
中科院分区：
文献类型：
--
作者：
Kawamura T;Kawatani M;Muroi M;Kondoh Y;Futamura Y;Aono H;Tanaka M;Honda K;Osada H
由于最近的出版物表明癌细胞的存活依赖于 MTH1 来避免氧化核苷酸掺入细胞 DNA，因此 MTH1 作为潜在的癌症治疗靶点引起了人们的关注。在这项研究中，我们通过化学阵列筛选鉴定了新的基于嘌呤的 MTH1 抑制剂。然而，尽管本研究中确定的 MTH1 抑制剂针对细胞 MTH1，但与最近报道的一流抑制剂相比，它们对癌细胞仅表现出较弱的细胞毒性。我们进行了蛋白质组分析，以研究化学上不同的 MTH1 抑制剂诱导癌细胞死亡的作用模式，并发现一流的 MTH1 抑制剂之间存在机制差异。特别是，我们确定微管蛋白是 TH287 和 TH588 负责抗肿瘤作用的主要靶标，尽管其在体外具有纳摩尔 MTH1 抑制活性。此外，MTH1的过度表达并不能挽救细胞免受MTH1抑制剂诱导的细胞死亡，并且siRNA介导的MTH1敲低也不能抑制癌细胞生长。综上所述，我们得出的结论是，MTH1 抑制剂的细胞毒性可归因于脱靶效应，并且 MTH1 对于癌细胞的存活并不是必需的。
Since recent publications suggested that the survival of cancer cells depends on MTH1 to avoid incorporation of oxidized nucleotides into the cellular DNA, MTH1 has attracted attention as a potential cancer therapeutic target. In this study, we identified new purine-based MTH1 inhibitors by chemical array screening. However, although the MTH1 inhibitors identified in this study targeted cellular MTH1, they exhibited only weak cytotoxicity against cancer cells compared to recently reported first-in-class inhibitors. We performed proteomic profiling to investigate the modes of action by which chemically distinct MTH1 inhibitors induce cancer cell death, and found mechanistic differences among the first-in-class MTH1 inhibitors. In particular, we identified tubulin as the primary target of TH287 and TH588 responsible for the antitumor effects despite the nanomolar MTH1-inhibitory activity in vitro. Furthermore, overexpression of MTH1 did not rescue cells from MTH1 inhibitor–induced cell death, and siRNA-mediated knockdown of MTH1 did not suppress cancer cell growth. Taken together, we conclude that the cytotoxicity of MTH1 inhibitors is attributable to off-target effects and that MTH1 is not essential for cancer cell survival.