Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt.

Détails

ID Serval
serval:BIB_876BE72DFD51
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt.
Périodique
Journal of Biological Chemistry
Auteur(s)
Bezzi M., Hasmim M., Bieler G., Dormond O., Rüegg C.
ISSN
0021-9258 (Print)
ISSN-L
0021-9258
Statut éditorial
Publié
Date de publication
2003
Peer-reviewed
Oui
Volume
278
Numéro
44
Pages
43603-43614
Langue
anglais
Résumé
Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (HUVEC) adhesion, migration, and survival, three events essential for angiogenesis. Zoledronate inhibited HUVEC adhesion mediated by integrin alphaVbeta3, but not alpha5beta1, blocked migration and disrupted established focal adhesions and actin stress fibers without modifying cell surface integrin expression level or affinity. Zoledronate treatment slightly decreased HUVEC viability and strongly enhanced tumor necrosis factor (TNF)-induced cell death. HUVEC treated with zoledronate and TNF died without evidence of enhanced annexin-V binding, chromatin condensation, or nuclear fragmentation and caspase dependence. Zoledronate inhibited sustained phosphorylation of focal adhesion kinase (FAK) and in combination with TNF, with and without interferon (IFN) gamma, of protein kinase B (PKB/Akt). Constitutive active PKB/Akt protected HUVEC from death induced by zoledronate and TNF/IFNgamma. Phosphorylation of c-Src and activation of NF-kappaB were not affected by zoledronate. Clodronate had no effect on HUVEC adhesion, migration, and survival nor did it enhanced TNF cytotoxicity. Taken together these data demonstrate that zoledronate sensitizes endothelial cells to TNF-induced, caspase-independent programmed cell death and point to the FAK-PKB/Akt pathway as a novel zoledronate target. These results have potential implications to the clinical use of zoledronate as an anti-angiogenic or anti-cancer agent.
Mots-clé
Adenoviridae/genetics, Angiogenesis Inhibitors/pharmacology, Annexin A5/metabolism, Apoptosis, Cell Adhesion/drug effects, Cell Death, Cell Membrane/metabolism, Cell Movement/drug effects, Cell Survival/drug effects, Cells, Cultured, Clodronic Acid/pharmacology, Coloring Agents/pharmacology, Diphosphonates/pharmacology, Electroporation, Endothelial Cells/drug effects, Endothelial Cells/pathology, Endothelium, Vascular/cytology, Enzyme Activation, Flow Cytometry, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Imidazoles/pharmacology, Integrin alpha5beta1/metabolism, Integrin alphaVbeta3/metabolism, Microscopy, Fluorescence, Phosphorylation, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Tumor Necrosis Factor-alpha/metabolism, Umbilical Veins/cytology
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/01/2008 9:36
Dernière modification de la notice
08/05/2019 21:29
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