RRC ID 63354
Author Fujita H, Utsumi T, Muranaka S, Ogino T, Yano H, Akiyama J, Yasuda T, Utsumi K.
Title Involvement of Ras/extracellular signal-regulated kinase, but not Akt pathway in risedronate-induced apoptosis of U937 cells and its suppression by cytochalasin B.
Journal Biochem Pharmacol
Abstract Although risedronate, a nitrogen containing bisphosphonate (BPs), strongly inhibits bone resorption by enhanced apoptosis of osteoclasts, its mechanism remained unclear. In this study, we investigated the molecular mechanism of risedronate-induced apoptosis of U937 cells, with a focus on extracellular signal-regulated kinase 1/2 (ERK 1/2) and protein kinase B (Akt) pathways, mitochondria-mediated apoptosis, and the effect of disruption of the actin cytoskeleton. Risedronate facilitated the relocation of Ras from membrane to cytosol through inhibited isoprenylation. Accordingly, risedronate suppressed the phosphorylation of ERK 1/2, a downstream survival signaling kinase of Ras, affected the intracellular distribution of Bcl-xL, and induced the mitochondrial membrane depolarization, cytochrome c release, activated caspase cascade and DNA fragmentation. The risedronate-induced apoptosis was effectively suppressed with cyclosporine A plus trifluoperazine, potent inhibitors of mitochondrial membrane permeability transition (MPT). The risedronate-induced apoptosis was independent of Akt, another cAMP-dependent survival signaling kinase. Risedronate facilitated dephosphorylation of Bad at Ser112, an ERK phosphorylation site, but not at Ser136, an Akt phosphorylation site. All of these apoptosis-related changes induced by risedronate were strongly suppressed by cytochalasin B, an inhibitor of actin filament polymerization. These results indicate that risedronate-induced apoptosis in U937 cells involves Ras/ERK, but not Akt signaling pathway, and is dependent on MPT, and that disruption of the actin cytoskeleton inhibits the risedronate-induced apoptosis at its early step.
Volume 69(12)
Pages 1773-84
Published 2005-6-15
DOI 10.1016/j.bcp.2005.03.006
PII S0006-2952(05)00155-3
PMID 15869745
MeSH Apoptosis / drug effects* Apoptosis / physiology Cytochalasin B / pharmacology* Etidronic Acid / analogs & derivatives* Etidronic Acid / antagonists & inhibitors* Etidronic Acid / pharmacology* Extracellular Signal-Regulated MAP Kinases / physiology* Humans Intracellular Membranes / drug effects Intracellular Membranes / physiology Membrane Potentials / drug effects Membrane Potentials / physiology Mitochondria / drug effects Mitochondria / physiology Protein Serine-Threonine Kinases / physiology* Proto-Oncogene Proteins / physiology* Proto-Oncogene Proteins c-akt Risedronic Acid Signal Transduction / drug effects Signal Transduction / physiology Trifluoperazine / pharmacology U937 Cells ras Proteins / physiology*
IF 4.96
Human and Animal Cells U-937 DE-4(RCB0435)