Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl.
Conventional cancer therapies are based on preferential killing of tumor cells by DNA damage. Previous work showed that, for certain cell types, loss of integrin-mediated adhesion decreased the apoptotic response to DNA damage because of decreased p53 levels after detachment from the extracellular matrix. Integrin ligation restored p53 and sensitivity to DNA damage. In this study, we show that c-Abl mediates a second pathway by which adhesion to extracellular matrix regulates cell killing by chemotherapeutic agents 5-arabinofuranosylcytosine, cisplatin, and camptothecin. Activation of c-Abl tyrosine kinase by DNA damage requires cell adhesion. Abl-dependent stabilization of p73, a p53-related proapoptotic transcription factor, is also adhesion-dependent. Sensitivity to the Abl inhibitor STI571 suggests differential utilization of the p53 and c-Abl/p73 pathways by different tumor cell lines. These data suggest that killing of p53-negative tumor cells by chemotherapy would be enhanced by integrin ligation to activate the alternative c-Abl/p73 pathway.
Truong
Tony
T
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Sun
Guizhen
G
Doorly
Michael
M
Wang
Jean Y J
JY
Schwartz
Martin Alexander
MA
D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002455:Cell Division; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D005353:Fibronectins / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D005353:Fibronectins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003561:Cytarabine; D016315:Proto-Oncogene Proteins c-abl