title: Adhesion to fibronectin selectively protects Bcr-Abl+ cells from DNA damage-induced apoptosis.
abstract: The phenotype of Bcr-Abl-transformed cells is characterized by a growth factor-independent survival and a reduced susceptibility to apoptosis. Furthermore, Bcr-Abl kinase alters adhesion features by phosphorylating cytoskeletal and/or signaling proteins important for integrin function. Integrin-mediated adhesion to extracellular matrix molecules is critical for the regulation of growth and apoptosis. However, effects of integrin signaling on regulation of apoptosis in cells expressing Bcr-Abl are largely unknown. The influence of adhesion on survival and apoptosis in Bcr-Abl+ and Bcr-Abl- BaF3 cells was investigated. p185bcr-abl-transfected BaF3 cells preadhered to immobilized fibronectin had a significant survival advantage and reduced susceptibility to apoptosis following gamma-irradiation when compared with the same cells grown on laminin, on polylysin, or in suspension. Both inhibition of Bcr-Abl kinase by STI571 and inhibition of specific adhesion reversed the fibronectin-mediated antiapoptotic effect in BaF3p185. The DNA damage response of Bcr-Abl- BaF3 cells was not affected by adhesion to fibronectin. In contrast to parental BaF3 cells, BaF3p185 adherent to fibronectin did not release cytochrome c to the cytosol following irradiation. The fibronectin-mediated antiapoptotic mechanism in Bcr-Abl-active cells was not mediated by overexpression of Bcl-XL or Bcl-2 but required an active phosphatidylinositol 3-kinase (PI-3K). Kinase-active Bcr-Abl in combination with fibronectin-induced integrin signaling led to a hyperphosphorylation of AKT. Thus, cooperative activation of PI-3K/AKT by Bcr-Abl and integrins causes synergistic protection of Bcr-Abl+ cells from DNA damage-induced apoptosis.
authors.affiliation: Dr Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany.
authors.forename: H
authors.initials: H
authors.lastname: van der Kuip
authors.forename: A W
authors.initials: AW
authors.lastname: Goetz
authors.forename: C
authors.initials: C
authors.lastname: Miething
authors.forename: J
authors.initials: J
authors.lastname: Duyster
authors.forename: W E
authors.initials: WE
authors.lastname: Aulitzky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001549:Benzamides; D002448:Cell Adhesion / Q000502:physiology*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000737:chemistry*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D005720:Gamma Rays; D005786:Gene Expression Regulation; D000068877:Imatinib Mesylate; D020287:In Situ Nick-End Labeling; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000201:enzymology; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D014162:Transfection; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D001549:Benzamides; D004791:Enzyme Inhibitors; D005353:Fibronectins; D016023:Integrins; D007377:Interleukin-3; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D000068877:Imatinib Mesylate; D004247:DNA; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt