Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA.
Xiangya School of Medicine, Central South University, 410008, Changsha, Hunan, China.
Cell Death Dis. 2018 Sep 24;9(10):986. doi: 10.1038/s41419-018-1040-9.
Lung cancer is the leading cause of death in the United States, with non-small cell lung cancers (NSCLC) accounting for 85% of all cases. By analyzing the expression profile of the pro-apoptotic and anti-apoptotic proteins, we have assigned NSCLCs into two distinct groups. While single agent treatment with the BCL-2/BCL-xL/BCL-w inhibitor ABT-263 (navitoclax) did not trigger apoptosis in either group, cells with a moderate to high level of MCL-1 expression were sensitive to ABT-263 treatment when MCL-1 expression was suppressed with a gene-specific siRNA. In contrast, those with a low MCL-1 expression did not undergo apoptosis upon combination treatment with ABT-263 and MCL-1 siRNA. Further studies revealed that cells with a low MCL-1 expression had low mitochondrial priming, and treatment with the chemotherapy drug docetaxel raised the mitochondrial priming level and consequently sensitized cells to ABT-263. These results establish a rationale for molecular profiling and a therapeutic strategy to treat NSCLC patients with pro-apoptotic anti-cancer drugs based on their MCL-1 expression level.
肺癌是美国的主要致死原因，其中非小细胞肺癌（NSCLC）占所有病例的 85%。通过分析促凋亡和抗凋亡蛋白的表达谱，我们将 NSCLC 分为两个截然不同的组。虽然用 BCL-2/BCL-xL/BCL-w 抑制剂 ABT-263（navitoclax）单药治疗并没有在任何一组中引发细胞凋亡，但当用基因特异性 siRNA 抑制 MCL-1 表达时，中高表达 MCL-1 的细胞对 ABT-263 治疗敏感。相比之下，那些 MCL-1 表达水平低的细胞在联合使用 ABT-263 和 MCL-1 siRNA 时不会发生细胞凋亡。进一步的研究表明，MCL-1 表达水平低的细胞线粒体引发水平低，用化疗药物多西他赛处理会提高线粒体引发水平，从而使细胞对 ABT-263 敏感。这些结果为基于 MCL-1 表达水平用促凋亡抗癌药物对 NSCLC 患者进行分子谱分析和治疗策略提供了依据。
