Abrogation of the cell death response to oxidative stress by the c-Abl tyrosine kinase inhibitor STI571.
Normal aerobic metabolism is associated with the production of reactive oxygen species (ROS) and, consequently, the induction of apoptosis and necrosis. The cell death response to oxidative stress is thought to contribute to aging, neurological degeneration, and other disorders. ROS-induced apoptosis and necrosis involves activation of the cytoplasmic c-Abl tyrosine kinase and thereby signaling to mitochondria. Herein, we show that STI571, an inhibitor of Bcr-Abl in chronic myelogenous leukemia, blocks activation of c-Abl in the response of mouse embryo fibroblasts and human U-937 myeloid leukemia cells to hydrogen peroxide (H(2)O(2)). Immunofluorescence microscopy and subcellular fractionation studies demonstrate that STI571 decreases H(2)O(2)-induced targeting of c-Abl to mitochondria in the two cell types by 59 to 85%. The results also show that STI571 attenuates H(2)O(2)-induced loss of the mitochondrial transmembrane potential. In concert with these effects, STI571 inhibits the death response to H(2)O(2) exposure by 40 to 80% depending on the cell type. These findings indicate that inhibition of c-Abl signaling by STI571 attenuates mitochondrial dysfunction and cell death in the cellular response to oxidative stress.
Kumar
Shailendra
S
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mishra
Neerad
N
Raina
Deepak
D
Saxena
Satya
S
Kufe
Donald
D
D000818:Animals; D017209:Apoptosis; D001549:Benzamides; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl