Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status
Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status
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DOI：
10.1124/mol.106.028837
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Heymann, D.
中科院分区：
文献类型：
--
作者：
Ory, B.;Blanchard, F.;Heymann, D.
在几种不同p53和视网膜母细胞瘤（Rb）状态的骨肉瘤细胞系中，研究了含氮双膦酸唑来膦酸（Zol）对细胞影响的分子机制。Zol抑制细胞增殖，增加非典型凋亡。Zol对增殖的影响是由于在S内DNA损伤检查点激活后，细胞周期阻滞在S期和G(2)/M期，P-ATR、P-chk1、Wee1和P-cdc2水平增加，cdc25c水平降低，而与p53和Rb状态无关。此外，Zol诱导的非典型凋亡不依赖于caspase的激活，其特征是细胞核改变，Bax表达增加，Bcl-2水平降低。此外，Zol可以独立于p53上调线粒体通透性，这与凋亡诱导因子（AIF）和内切酶- g （EndoG）的易位有关。Zol还扰乱细胞骨架组织和细胞连接，抑制细胞迁移和局灶黏附激酶的磷酸化。治疗癌症遇到的主要困难与p53、Rb等关键基因或影响许多肿瘤细胞携带的caspase信号传导的蛋白质的突变有关。我们首次证明了唑来膦酸通过AIF和EndoG易位激活DNA损伤s期检查点和线粒体途径，并通过这些潜在突变抑制细胞增殖和诱导细胞死亡。因此，唑来膦酸可能被认为是骨肉瘤临床试验中有效的治疗药物，在骨肉瘤中p53和Rb突变经常发生，而目前传统化疗药物治疗无效。
The molecular mechanisms responsible for the cellular effects of the nitrogen-containing bisphosphonate zoledronic acid (Zol) were assessed on several osteosarcoma cell lines differing in their p53 and retinoblastoma (Rb) status. Zol inhibited cell proliferation and increased atypical apoptosis. The Zol effects on proliferation were due to cell cycle arrest in S and G(2)/M phases subsequent to the activation of the intra-S DNA damage checkpoint with an increase in P-ATR, P-chk1, Wee1, and P-cdc2 levels and a decrease in cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of caspase activation, and it was characterized by nuclear alterations, increased Bax expression, and reduced Bcl-2 level. Furthermore, mitochondrial permeability was up-regulated by Zol independently of p53 in association with the translocation of apoptosis-inducing factor (AIF) and endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization and cell junctions and inhibited cell migration and phosphorylation of focal adhesion kinases. The main difficulty encountered in treating cancer relates to mutations in key genes such as p53, Rb, or proteins affecting caspase signaling carried by many tumor cells. We have demonstrated for the first time that zoledronic acid activated the DNA damage S-phase checkpoint and the mitochondrial pathway via AIF and EndoG translocation, and it inhibited cell proliferation and induced cell death, bypassing these potentials mutations. Therefore, zoledronic acid may be considered as an effective therapeutic agent in clinical trials of osteosarcoma in which mutation for p53 and Rb very often occur, and where current treatment with traditional chemotherapeutic agents is ineffective.