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Selective targeting of c-Abl via a cryptic mitochondrial targeting signal activated by cellular redox status in leukemic and breast cancer cells.
- Source :
-
Pharmaceutical research [Pharm Res] 2012 Aug; Vol. 29 (8), pp. 2317-28. Date of Electronic Publication: 2012 May 02. - Publication Year :
- 2012
-
Abstract
- Purpose: 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.<br />Methods: 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.<br />Results: 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.<br />Conclusions: 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.
- Subjects :
- Amino Acid Sequence
Animals
COS Cells
Cell Death
Cell Line, Tumor
Chlorocebus aethiops
Female
Gene Expression
Humans
Leukemia genetics
Leukemia pathology
Mammary Neoplasms, Animal genetics
Mammary Neoplasms, Animal pathology
Mice
Mitochondria genetics
Mitochondria pathology
Molecular Sequence Data
Oxidative Stress
Protein Transport
Proto-Oncogene Proteins c-abl analysis
Proto-Oncogene Proteins c-abl genetics
Recombinant Fusion Proteins analysis
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Leukemia metabolism
Mammary Neoplasms, Animal metabolism
Mitochondria metabolism
Proto-Oncogene Proteins c-abl metabolism
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-904X
- Volume :
- 29
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Pharmaceutical research
- Publication Type :
- Academic Journal
- Accession number :
- 22549737
- Full Text :
- https://doi.org/10.1007/s11095-012-0758-9