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

Manuela Bezzi, Meriem Hasmim, Grégory Bieler, Olivier Dormond, Curzio Rüegg*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

135 Citations (Scopus)

Abstract

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 αvβ3, but not α 5β1, 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) γ, of protein kinase B (PKB/Akt). Constitutive active PKB/Akt protected HUVEC from death induced by zoledronate and TNF/IFNγ. Phosphorylation of c-Src and activation of NF-κB 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.

Original languageEnglish
Pages (from-to)43603-43614
Number of pages12
JournalJournal of Biological Chemistry
Volume278
Issue number44
DOIs
Publication statusPublished - 31 Oct 2003
Externally publishedYes

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this