Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology.
Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology.
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DOI：
10.1038/srep20441
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发表时间：
2016-02-04
影响因子：
4.6
通讯作者：
Xie L
中科院分区：
文献类型：
--
作者：
Hart T;Dider S;Han W;Xu H;Zhao Z;Xie L
二甲双胍，一种用于治疗2型糖尿病的药物，在部分患者中显示出抗癌作用，但导致这种多效性作用的直接分子和基因相互作用尚未得到充分探索。为了使二甲双胍成为一种精确的抗癌药物，我们开发了一种新的结构系统药理学方法来阐明二甲双胍的分子基础和作用的遗传生物标志物。我们结合结构基因组学、功能基因组学和相互作用组学数据，将结构蛋白质组学尺度的药物靶点鉴定与网络生物学分析相结合。通过搜索人类结构蛋白质组，我们确定了20个推测的二甲双胍结合靶点及其相互作用模型。我们通过实验验证了二甲双胍与我们排名靠前的激酶靶点之间的相互作用。值得注意的是，激酶，特别是SGK1和EGFR被确定为二甲双胍的关键分子靶点。随后，我们将这些假定的结合靶点与不直接结合二甲双胍，但其表达通过蛋白质-蛋白质相互作用被二甲双胍改变的基因联系起来，并确定了二甲双胍表型反应的网络生物标志物。遗传网络中的分子靶点和关键节点与现有的实验证据基本一致。它们的相互作用会受到观察到的癌症突变的影响。这项研究将为重新利用二甲双胍进行安全、有效、个性化的治疗提供新的思路。
Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies.