The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFκB pathway in osteosarcoma cells
The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFκB pathway in osteosarcoma cells
复制标题
DOI：
10.1038/sj.bjp.0706373
复制
发表时间：
2005-11-01
影响因子：
7.3
通讯作者：
Hirata, M
中科院分区：
文献类型：
--
作者：
Inoue, R;Matsuki, N;Hirata, M
1双膦酸盐通过诱导细胞凋亡抑制肿瘤细胞生长和骨吸收。然而，关于药物诱导细胞凋亡的机制知之甚少。本研究的目的是确定阿仑膦酸钠（一种含氮双膦酸盐）对主要细胞存活途径磷酸肌醇3-激酶(PI3K)-Akt-NF κ B通路的影响PI3K-Akt-NF κ B通路在肿瘤坏死因子- α或胰岛素处理的骨肉瘤细胞系MG-63中被激活。Saos-2也用于一些实验。通过磷脂酰肌醇3,4,5-三磷酸（PtdIns(3,4,5)P-3）的产生，PI3K活性的增加，Akt在丝氨酸473和苏氨酸308位点的磷酸化，核因子κ B激酶（IKK）抑制剂活性的增加以及I κ B的磷酸化及其随后的降解来评估这一点在肿瘤坏死因子- α或胰岛素刺激前，100 μ M阿仑膦酸钠预处理24 h，部分抑制I κ B磷酸化和降解。这些事件被更清晰地观察到在水解酶的抑制剂的存在,负责我κB .药物的降解也部分地抑制IKK的活动,但几乎完全抑制了一种蛋白激酶的磷酸化和生产PtdIns(3、4、5)P3.4 alendronate我κB磷酸化的抑制效果和退化是不减的外源添加geranylgeraniol胞质isoprenyl脂质substrate.5补充本研究结果表明，阿仑膦酸钠在PI3K激活点抑制PI3K- akt - nf κ B细胞存活通路，提示阿仑膦酸钠存在新的靶点。
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-NF kappa B pathway, the major cell survival pathway.2 The PI3K-Akt-NF kappa B pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-alpha 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 kappa B (I kappa B) kinase (IKK) and finally phosphorylation of I kappa B and its subsequent degradation.3 Pretreatment with alendronate at 100 mu M for 24 h prior to the stimulation with tumor necrosis factor-alpha or insulin partially inhibited the I kappa B phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of I kappa B. 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)P3.4 The inhibitory effect of alendronate on I kappa B 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-NF kappa B cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.