Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation
Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation
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DOI：
10.1158/0008-5472.can-08-2689
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Tomida, Akihiro
中科院分区：
文献类型：
--
作者：
Saito, Sakae;Furuno, Aki;Tomida, Akihiro
葡萄糖剥夺是发生在实体肿瘤中的一种细胞状况，它激活了未折叠蛋白反应（UPR）。UPR的一个关键特征是转录程序的激活，它允许细胞在应激条件下存活。在这里，我们展示了UPR转录程序被抗糖尿病的双胍类药物二甲双胍、丁双胍和苯双胍破坏，这取决于细胞葡萄糖的可用性。这些药物抑制UPR转录激活因子XBP1和ATF4的产生，并在葡萄糖剥夺期间诱导大量细胞死亡，抗肿瘤大环化合物versipelostatin也是如此。基因表达谱显示，由广泛的葡萄糖剥夺诱导基因决定的双胍类和version - ostatin的作用模式具有显著的相似性。重要的是，在葡萄糖剥夺过程中，大多数双胍抑制基因与tunicamycin（一种化学UPR诱导剂）诱导的基因重叠。基因表达谱还确定了药物驱动的特征，作为发现药理学UPR调节剂的工具。我们的研究结果表明，在葡萄糖剥夺过程中破坏UPR可能是选择性杀死癌细胞的一种有吸引力的方法，并可能为开发针对UPR的实体肿瘤药物提供化学基因组基础。[癌症研究2009；69 (10): 4225 - 34)
Glucose deprivation, a cell condition that occurs in solid tumors, activates the unfolded protein response (UPR). A key feature of the UPR is the transcription program activation, which allows the cell to survive under stress conditions. Here, we show that the UPR transcription program is disrupted by the antidiabetic biguanides metformin, buformin, and phenformin depending on cellular glucose availability. These drugs inhibit production of the UPR transcription activators XBP1 and ATF4 and induce massive cell death during glucose deprivation as did the antitumor macrocyclic compound versipelostatin. Gene expression profiling shows remarkable similarity in the modes of action of biguanides and versipelostatin determined by the broad range of glucose deprivation-inducible genes. Importantly, during glucose deprivation, most of the biguanide suppression genes overlap with the genes induced by tunicamycin, a chemical UPR inducer. Gene expression profiling also identifies drug-driven signatures as a tool for discovering pharmacologic UPR modulators. Our findings show that disrupting the UPR during glucose deprivation could he an attractive approach for selective cancer cell killing and could provide a chemical genomic basis for developing UPR-targeting drugs against solid tumors. [Cancer Res 2009;69(10):4225-34]