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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1532-1541
NEOPLASIA
Adhesion to fibronectin selectively protects Bcr-Abl+
cells from DNA damage-induced apoptosis
Heiko van der Kuip,
Alexander W. Goetz,
Cornelius Miething,
Justus Duyster, and
Walter E. Aulitzky
From the Dr Margarete Fischer-Bosch Institute for
Clinical Pharmacology, Stuttgart, Germany; Department of Internal
Medicine, Oncology and Hematology, Robert Bosch Hospital, Stuttgart,
Germany; and Department of Internal Medicine III, Technical University
of Munich, Germany.
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  -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.
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