Selective targeting of c-Abl via a cryptic mitochondrial targeting signal activated by cellular redox status in leukemic and breast cancer cells.
Selective targeting of c-Abl via a cryptic mitochondrial targeting signal activated by cellular redox status in leukemic and breast cancer cells.
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DOI：
10.1007/s11095-012-0758-9
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发表时间：
2012-08
影响因子：
3.7
通讯作者：
Lim CS
中科院分区：
文献类型：
--
作者：
Constance JE;Despres SD;Nishida A;Lim CS
在细胞应激条件下，酪氨酸激酶c-Abl定位于线粒体，促进细胞凋亡。然而，c-Abl并没有直接作用于线粒体。将c-Abl融合到由活性氧簇(ROS)激活的线粒体易位信号(MTS)上，将选择性地靶向表现ROS表型升高的癌细胞的线粒体。线粒体靶向的c-Abl因此会导致恶性细胞死亡。共聚焦显微镜被用来确定异位表达的c-Abl-EGFP/CMTs融合在三个细胞系(K562、Cos-7和1471.1)上的线粒体共定位，这些细胞系具有不同水平的基础(和药物调节的)ROS。用指示剂染色法定量测定ROS。用流式细胞术检测线粒体c-Abl对7-AAD的DNA可及性。CMTs和CMTs/c-Abl融合以ROS和PKC依赖的方式共定位于白血病(K562)和乳腺癌(1471.1)表型(而不是Cos-7成纤维细胞)的线粒体。我们通过证明CMTs和Abl/CMTs融合选择性地靶向于K562白血病和乳腺癌1471.1细胞的线粒体，证实并延长了氧化应激激活的CMTs的易位。当c-Abl靶向线粒体外膜而不是基质时，可诱导K562白血病细胞死亡。
The tyrosine kinase c-Abl localizes to the mitochondria under cell stress conditions and promotes apoptosis. However, c-Abl has not been directly targeted to the mitochondria. Fusing c-Abl to a mitochondrial translocation signal (MTS) that is activated by reactive oxygen species (ROS) will selectively target the mitochondria of cancer cells exhibiting an elevated ROS phenotype. Mitochondrially targeted c-Abl will thereby induce malignant cell death. Confocal microscopy was used to determine mitochondrial colocalization of ectopically expressed c-Abl-EGFP/cMTS fusion across three cell lines (K562, Cos-7, and 1471.1) with varying levels of basal (and pharmacologically modulated) ROS. ROS were quantified by indicator dye assay. The functional consequences of mitochondrial c-Abl were assessed by DNA accessibility to 7-AAD using flow cytometry. The cMTS and cMTS/c-Abl fusions colocalized to the mitochondria in leukemic (K562) and breast (1471.1) cancer phenotypes (but not Cos-7 fibroblasts) in a ROS and PKC dependent manner. We confirm and extend oxidative stress activated translocation of the cMTS by demonstrating that the cMTS and Abl/cMTS fusion selectively target the mitochondria of K562 leukemia and mammary adenocarcinoma 1471.1 cells. c-Abl induced K562 leukemia cell death when targeted to the matrix but not the outer membrane of the mitochondria.
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