Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIα protein levels and decreasing sensitivity to topoisomerase-targeted drugs
Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIα protein levels and decreasing sensitivity to topoisomerase-targeted drugs
复制标题
DOI：
10.1124/mol.105.014753
复制
发表时间：
2005-12-01
影响因子：
3.6
通讯作者：
Hendershot, LM
中科院分区：
文献类型：
--
作者：
Gray, MD;Mann, M;Hendershot, LM
已经鉴定了多种对实体瘤有活性的化学治疗剂。然而，耐药性仍然是制定治疗方案的一个重要障碍。尽管获得性耐药性已受到广泛关注，但也已描述了多种生理途径，其降低先前未治疗的肿瘤对细胞毒性抗肿瘤剂的敏感性。用改变内质网（ER）环境并激活未折叠蛋白反应（UPR）的药理学试剂处理细胞可使细胞对拓扑异构酶II毒物具有抗性。我们描述的实验表明，哺乳动物ER应激反应的激活是必要的和足够的，以降低拓扑异构酶II α蛋白水平，并使细胞耐依托泊苷，拓扑异构酶II靶向药物。这不是由作为这种应答的标志的BiP水平升高引起的，因为已经被工程化以过表达BiP的细胞系不显示对依托泊苷的抗性增加。UPR被证明是改变药物敏感性所必需的，因为BiP过表达细胞系，其不能激活UPR，并没有显示拓扑异构酶II水平降低或对依托泊苷的抗性增加。未折叠蛋白的短暂过表达激活了UPR，并导致细胞中拓扑异构酶II α蛋白的同时丢失，这表明UPR激活足以导致之前在药理学诱导UPR时观察到的拓扑异构酶II水平的变化。
A wide range of chemotherapeutic agents has been identified that are active against solid tumors. However, resistance remains an important obstacle to the development of curative regimens. Whereas much attention has been paid to acquired drug resistance, a variety of physiological pathways also have been described that reduce the sensitivity of previously untreated tumors to cytotoxic antitumor agents. Treatment of cells with pharmacological agents that alter the environment of the endoplasmic reticulum (ER) and activate the unfolded protein response (UPR) can render cells resistant to topoisomerase II poisons. We describe experiments showing that activation of the mammalian ER stress response is both necessary and sufficient to decrease topoisomerase II alpha protein levels and to render cells resistant to etoposide, a topoisomerase II-targeting drug. This is not caused by the elevated levels of BiP that are a hallmark of this response, because a cell line that has been engineered to overexpress BiP does not show increased resistance to etoposide. The UPR was shown to be required for altered drug sensitivity, because the BiP-overexpressing cell line, which is unable to activate the UPR, did not show decreased topoisomerase II levels or increased resistance to etoposide in response to stress conditions. The transient overexpression of an unfolded protein activated the UPR and led to the concomitant loss of topoisomerase II alpha protein from the cells, demonstrating that UPR activation is sufficient for the changes in topoisomerase II levels that had been observed previously with pharmacological induction of the UPR.