TY - JOUR
T1 - The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFκB pathway in osteosarcoma cells
AU - Inoue, Ryosuke
AU - Matsuki, Nori Aki
AU - Jing, Gao
AU - Kanematsu, Takashi
AU - Abe, Kihachiro
AU - Hirata, Masato
PY - 2005/11
Y1 - 2005/11
N2 - 1. Bisphosphonates are inhibitors of tumor cell growth as well as of bone resorption by inducing cell apoptosis. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. The aim of the present study was to determine the effect of alendronate, one of the nitrogen-containing bisphosphonates on the phoshoinositide 3-kinase (PI3K)-Akt-NFκB pathway, the major cell survival pathway. 2. The PI3K-Akt-NFκB pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-α or insulin. Saos-2 was also used in some experiments. This was assessed by the production of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3), increased PI3K activity, phosphorylation of Akt at serine 473 and threonine 308, increase in activity of the inhibitor of nuclear factor κB (IκB) kinase (IKK) and finally phosphorylation of IκB and its subsequent degradation. 3. Pretreatment with alendronate at 100 μM for 24 h prior to the stimulation with tumor necrosis factor-α or insulin partially inhibited the IκB phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of IκB. The drug also partially inhibited the activity of IKK, but almost fully inhibited the phosphorylation of Akt and the production of PtdIns(3,4,5)P 3. 4. The inhibitory effect of alendronate on IκB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate. 5. The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFκB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.
AB - 1. Bisphosphonates are inhibitors of tumor cell growth as well as of bone resorption by inducing cell apoptosis. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. The aim of the present study was to determine the effect of alendronate, one of the nitrogen-containing bisphosphonates on the phoshoinositide 3-kinase (PI3K)-Akt-NFκB pathway, the major cell survival pathway. 2. The PI3K-Akt-NFκB pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-α or insulin. Saos-2 was also used in some experiments. This was assessed by the production of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3), increased PI3K activity, phosphorylation of Akt at serine 473 and threonine 308, increase in activity of the inhibitor of nuclear factor κB (IκB) kinase (IKK) and finally phosphorylation of IκB and its subsequent degradation. 3. Pretreatment with alendronate at 100 μM for 24 h prior to the stimulation with tumor necrosis factor-α or insulin partially inhibited the IκB phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of IκB. The drug also partially inhibited the activity of IKK, but almost fully inhibited the phosphorylation of Akt and the production of PtdIns(3,4,5)P 3. 4. The inhibitory effect of alendronate on IκB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate. 5. The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFκB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.
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U2 - 10.1038/sj.bjp.0706373
DO - 10.1038/sj.bjp.0706373
M3 - Article
C2 - 16100524
AN - SCOPUS:27644568995
VL - 146
SP - 633
EP - 641
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 5
ER -