title: Ligand bound beta1 integrins inhibit procaspase-8 for mediating cell adhesion-mediated drug and radiation resistance in human leukemia cells.
abstract: BACKGROUND
  Chemo- and radiotherapeutic responses of leukemia cells are modified by integrin-mediated adhesion to extracellular matrix. To further characterize the molecular mechanisms by which beta1 integrins confer radiation and chemoresistance, HL60 human acute promyelocytic leukemia cells stably transfected with beta1 integrin and A3 Jurkat T-lymphoma cells deficient for Fas-associated death domain protein or procaspase-8 were examined.
  
  
  RESULTS
  Upon exposure to X-rays, Ara-C or FasL, suspension and adhesion (fibronectin (FN), laminin, collagen-1; 5-100 microg/cm(2) coating concentration) cultures were processed for measurement of apoptosis, mitochondrial transmembrane potential (MTP), caspase activation, and protein analysis. Overexpression of beta1 integrins enhanced the cellular sensitivity to X-rays and Ara-C, which was counteracted by increasing concentrations of matrix proteins in association with reduced caspase-3 and -8 activation and MTP breakdown. Usage of stimulatory or inhibitory anti beta1 integrin antibodies, pharmacological caspase or phosphatidylinositol-3 kinase (PI3K) inhibitors, coprecipitation experiments and siRNA-mediated beta1 integrin silencing provided further data showing an interaction between FN-ligated beta1 integrin and PI3K/Akt for inhibiting procaspase-8 cleavage.
  
  
  CONCLUSIONS
  The presented data suggest that the ligand status of beta1 integrins is critical for their antiapoptotic effect in leukemia cells treated with Ara-C, FasL or ionizing radiation. The antiapoptotic actions involve formation of a beta1 integrin/Akt complex, which signals to prevent procaspase-8-mediated induction of apoptosis in a PI3K-dependent manner. Antagonizing agents targeting beta1 integrin and PI3K/Akt signaling in conjunction with conventional therapies might effectively reduce radiation- and drug-resistant tumor populations and treatment failure in hematological malignancies.
authors.affiliation: Bundeswehr Institute of Radiobiology, Munich, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Estrugo
authors.forename: Alexander
authors.initials: A
authors.lastname: Fischer
authors.forename: Franziska
authors.initials: F
authors.lastname: Hess
authors.forename: Harry
authors.initials: H
authors.lastname: Scherthan
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
mesh_terms: D061945:Caspase Inhibitors; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003094:Collagen / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D039641:Integrin beta Chains / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D007797:Laminin / Q000494:pharmacology; D011835:Radiation Protection; D014965:X-Rays
chemical_list: D061945:Caspase Inhibitors; D005353:Fibronectins; D039641:Integrin beta Chains; D007797:Laminin; D003561:Cytarabine; D003094:Collagen