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首页> 外文期刊>Cell biology international. >Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells.
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Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells.

机译：抑制GGTase-I和FTase会破坏人PC-3前列腺癌细胞的细胞骨架组织。

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摘要

The mevalonate synthesis pathway produces intermediates for isoprenylation of small GTPases, which are involved in the regulation of actin cytoskeleton and cell motility. Here, we investigated the role of the prenylation transferases in the regulation of the cytoskeletal organization and motility of PC-3 prostate cancer cells. This was done by using FTI-277, GGTI-298 or NE-10790, the specific inhibitors of FTase (farnesyltransferase), GGTase (geranylgeranyltransferase)-I and -II, respectively. Treatment of PC-3 cells with GGTI-298 and FTI-277 inhibited migration and invasion in a time- and dose-dependent manner. This was associated with disruption of F-actin organization and decreased recovery of GFP-actin. Immunoblot analysis of various cytoskeleton-associated proteins showed that the most striking change in GGTI-298- and FTI-277-treated cells was a markedly decreased level of total and phosphorylated cofilin, whereas the level of cofilin mRNA was not decreased. The treatment of PC-3 cells with GGTI-298 also affected the dynamics of GFP-paxillin and decreased the levels of total and phosphorylated paxillin. The levels of phosphorylated FAK (focal adhesion kinase) and PAK (p-21-associated kinase)-2 were also lowered by GGTI-298, but levels of paxillin or FAK mRNAs were not affected. In addition, GGTI-298 had a minor effect on the activity of MMP-9. RNAi knockdown of GGTase-Ibeta inhibited invasion, disrupted F-actin organization and decreased the level of cofilin in PC-3 cells. NE-10790 did not have any effect on PC-3 prostate cancer cell motility or on the organization of the cytoskeleton. In conclusion, our results demonstrate the involvement of GGTase-I- and FTase-catalysed prenylation reactions in the regulation of cytoskeletal integrity and motility of prostate cancer cells and suggest them as interesting drug targets for development of inhibitors of prostate cancer metastasis.
机译：甲羟戊酸合成途径产生用于小GTP酶的异戊二烯化的中间体，其参与肌动蛋白细胞骨架和细胞运动的调节。在这里，我们调查了异戊二烯基转移酶在调节PC-3前列腺癌细胞的细胞骨架组织和运动中的作用。这是通过分别使用FTI-277，GGTI-298或NE-10790（FTase（法尼基转移酶），GGTase（香叶基香叶基转移酶）-I和-II的特异性抑制剂）来完成的。用GGTI-298和FTI-277处理PC-3细胞会以时间和剂量依赖性方式抑制迁移和侵袭。这与F-肌动蛋白组织的破坏和GFP-肌动蛋白的恢复降低有关。各种细胞骨架相关蛋白的免疫印迹分析表明，GGTI-298和FTI-277处理的细胞中最显着的变化是总和磷酸化的cofilin水平显着降低，而cofilin mRNA水平并未降低。 GGTI-298处理PC-3细胞也影响了GFP-paxillin的动力学，并降低了总和磷酸化paxillin的水平。 GGTI-298也降低了磷酸化的FAK（局灶性粘附激酶）和PAK（p-21相关激酶）-2的水平，但未影响paxillin或FAK mRNA的水平。此外，GGTI-298对MMP-9的活性影响较小。 RNAi的GGTase-Ibeta抑制了PC-3细胞的侵袭，破坏了F-肌动蛋白的组织并降低了cofilin的水平。 NE-10790对PC-3前列腺癌细胞的运动或细胞骨架的组织没有任何影响。总之，我们的结果表明，GGTase-I和FTase催化的异戊二烯化反应参与了前列腺癌细胞的细胞骨架完整性和运动性调节，并暗示它们是开发前列腺癌转移抑制剂的有趣药物靶标。

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