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MCL-1 dependency of cisplatin-resistant cancer cells

机译：顺铂耐药癌细胞的MCL-1依赖性

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The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADPribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-L-x. BCL-L-x was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings. (C) 2014 Elsevier Inc. All rights reserved.
机译：在顺二氨二氯铂（II）（CDDP，最有名的顺铂）中人类癌细胞系的选择伴随有定型改变，这些改变有助于获得CDDP耐药状态。因此，CDDP抗性通常会导致DNA修复酶聚（ADP-核糖）聚合酶-1（PARP1）的上调，从而导致聚（ADPribose）（PAR）修饰的蛋白质在细胞内积累。在这里，我们报告伴随CDDP抗性的另一种频繁变化，即抗凋亡BCL-2家族蛋白MCL-1的上调。 8个CDDP耐药癌细胞系中有6个表现出MCL-1蛋白表达水平增加，而只有少数细胞系过表达BCL-2或BCL-L-x。 8个癌细胞系中有6个的BCL-L-x降低。重要的是，过表达MCL-1的CDDP抗性细胞似乎“沉迷”于MCL-1，因为它们在RNA干扰或BH3模拟方尖碑对MCL-1表达的药理抑制作用下耗竭MCL-1后死亡。敲低PARP1不能成功降低MCL-1的表达，而耗竭或抑制MCL-1不能影响PARP1的活性。因此，两个抵抗机制没有通过直接的因果关系相互联系。重要的是，在异种移植小鼠体内，过表达CDDP的抗性，MCL-1过度表达的人类非小细胞肺癌对体内用obatoclax的单药治疗有反应，强调了这些发现的可能治疗意义。 （C）2014 Elsevier Inc.保留所有权利。

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