Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells
Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells
复制标题
DOI：
10.1016/j.bcp.2009.10.003
复制
发表时间：
2010-03-01
影响因子：
5.8
通讯作者：
Monkkonen, Jukka
中科院分区：
文献类型：
--
作者：
Raikkonen, Johanna;Monkkonen, Hannu;Monkkonen, Jukka
越来越多的证据表明，唑来膦酸（ZOL），一种含氮的双膦酸盐（N-BP），能够通过抑制甲羟戊酸途径（MVP）中的法尼基焦磷酸合酶（FPPS）来影响肿瘤细胞。据信未异戊二烯化蛋白质的随后积累在很大程度上解释了ZOL的细胞毒性作用。FPPS抑制也导致异戊烯焦磷酸（IPP）和凋亡ATP类似物，AppPI的积累，但这种机制在双膦酸盐的细胞毒性作用的作用是不太清楚。由于MVP中间体的处理已被证明可以通过挽救蛋白质异戊二烯化来克服N-BP诱导的细胞凋亡，我们的目的是确定它们对ZOL诱导的IPP/AppPI积累的作用机制。有趣的是，结果显示，ZOL诱导的MCF-7细胞中IPP/AppPI积累被法尼醇降低，并且几乎完全被香叶基香叶醇和香叶基焦磷酸阻断。IPP和AppPI，IPP异构酶和氨酰-tRNA-合成酶，分别或蛋白质水平的FPPS的调节酶的功能没有受到影响的治疗。然而，3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）和未异戊二烯化Rap 1A的蛋白质水平被观察到强烈下调香叶基香叶醇和香叶基焦磷酸。这项研究代表了一个新的洞察MVP的中间体的作用机制FPPS抑制后的MVP的调节。这些数据表明，除了先前报道的对挽救蛋白质异戊二烯化的作用外，MVP中间体还可以通过HMGR下调抑制IPP/AppPI的积累来保持细胞活性。这支持了IPP/ApppI形成是ZOL抗癌作用的重要机制的假设。(c)2009 Elsevier Inc. All rights reserved.
Increasing evidence is accumulating that zoledronic acid (ZOL), a nitrogen-containing bisphosphonate (N-BP), is able to affect tumor cells by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). The consequent accumulation of unprenylated proteins is believed to largely account for the cytotoxic effects of ZOL. FPPS inhibition leads also to the accumulation of isopentenyl pyrophosphate (IPP) and the apoptotic ATP analog, ApppI, but the role of this mechanism in the cytotoxic action of bisphosphonates is less clear. Since treatment with MVP intermediates has been shown to overcome N-BP-induced apoptosis via rescuing protein prenylation, our aim here was to determine their mechanism of action on ZOL-induced IPP/ApppI accumulation.Interestingly, the results revealed that ZOL-induced IPP/ApppI accumulation in MCF-7 cells were decreased by farnesol, and almost completely blocked by geranylgeraniol and geranylpyrophosphate. The functionality of the regulatory enzymes of IPP and ApppI, IPP isomerase and aminoacyl-tRNA- synthase, respectively, or protein levels of FPPS were not affected by the treatments. However, the protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and unprenylated Rap1A were observed to be strongly downregulated by geranylgeraniol and geranylpyrophosphate.This study represents a novel insight into the mechanism of action of MVP intermediates on the regulation of MVP after FPPS inhibition. The data implies that in addition to the previously reported effects on rescuing protein prenylation, MVP intermediates can preserve cell activity by inhibiting the accumulation of IPP/ApppI via HMGR downregulation. This supports the hypothesis that IPP/ApppI formation is a significant mechanism in the anticancer action of ZOL. (c) 2009 Elsevier Inc. All rights reserved.