Integrins regulate the apoptotic response to DNA damage through modulation of p53.
p53 mediates apoptosis of cells after DNA damage including tumor cells after radiation or chemotherapy. Survival of isolated cancer cells after therapy leads to recurrence of therapy-resistant tumors. We now show that for some melanoma, sarcoma, or fibroblastic cell types that survive without integrin-mediated adhesion, apoptosis in response to DNA damage requires cell adhesion. This effect correlates with rapid changes in levels of p14/p19 Arf and its downstream component, p53. Killing of nonadherent cells is increased by treatment with antiintegrin antibodies or by increasing levels of p53 or Arf. Consistent with low p53 levels, suspended cells show chromosomal instability after irradiation. Thus, loss of normal adhesion in susceptible tumor cells during genotoxic stress may play a role in therapy resistance and promote survival of cells with aberrant DNA.
Lewis
Jean McArthur
JM
Department of Vascular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CVN228/VB4, La Jolla, CA 92037, USA.
Truong
Tony Nguyen
TN
Schwartz
Martin Alexander
MA
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000528:radiation effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival; D002869:Chromosome Aberrations / Q000528:radiation effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D005347:Fibroblasts; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins; D009928:Organ Specificity; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011839:Radiation, Ionizing; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016023:Integrins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases