Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions.
Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions.
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DOI：
10.1038/cddis.2014.475
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发表时间：
2014-11-13
影响因子：
9
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中科院分区：
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唑来膦酸（ZOL），一种含氮的双膦酸盐，通过诱导细胞凋亡或S期阻滞产生抗肿瘤作用，这取决于所测试的人类间皮瘤细胞。除了类异戊二烯，香叶基香叶醇，但不是法尼醇，否定这些ZOL诱导的效果，表明ZOL介导的效果是由于消耗的香叶基香叶基焦磷酸，这是小鸟嘌呤核苷酸结合调节蛋白（小G蛋白）的异戊二烯化过程的底物。ZOL处理的细胞降低了RhoA，Cdc42和Rab6的膜与细胞质组分的比例，但不太显着Rac1蛋白，表明这些蛋白可能是ZOL诱导的行动的目标。我们进一步分析了哪些小G蛋白负责三个ZOL诱导的效果，半胱天冬酶介导的细胞凋亡，S期阻滞和形态学变化，使用抑制剂各自的小G蛋白和siRNA Cdc42。ZOL诱导的细胞凋亡是由于Rab蛋白的异戊烯化不足，因为对Rab家族蛋白异戊烯化具有特异性的香叶基香叶基转移酶II的抑制剂，而不是其他抑制剂，激活了与ZOL相同的细胞凋亡途径。ZOL抑制内源性拓扑异构酶II活性，这与细胞凋亡和S期阻滞在各自的细胞，因为我们检测到相同的细胞周期变化依托泊苷处理的细胞。香叶基香叶基转移酶I和RhoA的抑制剂产生形态学变化和破坏肌动蛋白纤维结构，这两者与ZOL治疗的结果相似。这些数据表明，ZOL的抗肿瘤作用归因于抑制各自的小G蛋白的功能和拓扑异构酶II的活性，并建议细胞因子参与了细胞周期的差异变化。
Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, produced anti-tumor effects through apoptosis induction or S-phase arrest depending on human mesothelioma cells tested. An addition of isoprenoid, geranylgeraniol but not farnesol, negated these ZOL-induced effects, indicating that the ZOL-mediated effects were attributable to depletion of geranylgeranyl pyrophosphates which were substrates for prenylation processes of small guanine-nucleotide-binding regulatory proteins (small G proteins). ZOL-treated cells decreased a ratio of membrane to cytoplasmic fractions in RhoA, Cdc42 and Rab6 but less significantly Rac1 proteins, indicating that these proteins were possible targets for ZOL-induced actions. We further analyzed which small G proteins were responsible for the three ZOL-induced effects, caspase-mediated apoptosis, S-phase arrest and morphological changes, using inhibitors for respective small G proteins and siRNA for Cdc42. ZOL-induced apoptosis is due to insufficient prenylation of Rab proteins because an inhibitor of geranlygeranyl transferase II that was specific for Rab family proteins prenylation, but not others inhibitors, activated the same apoptotic pathways that ZOL did. ZOL suppressed an endogenous topoisomerase II activity, which was associated with apoptosis and S-phase arrest in respective cells because we detected the same cell cycle changes in etoposide-treated cells. Inhibitors for geranlygeranyl transferase I and for RhoA produced morphological changes and disrupted actin fiber structures, both of which were similar to those by ZOL treatments. These data demonstrated that anti-tumor effects by ZOL were attributable to inhibited functions of respective small G proteins and topoisomerase II activity, and suggested that cellular factors were involved in the differential cell cycle changes.
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影响因子：
33.6
作者：
Hutagalung AH;Novick PJ
通讯作者：
Novick PJ
影响因子：
5.8
作者：
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影响因子：
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作者：
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Green, JR
影响因子：
6.2
作者：
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通讯作者：
Rogers, MJ
DOI：
10.1038/nrc2608
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
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