The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling - Role in FTI enhancement of taxane and tamoxifen anti-tumor activity
The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling - Role in FTI enhancement of taxane and tamoxifen anti-tumor activity
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DOI：
10.1074/jbc.m503763200
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发表时间：
2005-09-02
影响因子：
4.8
通讯作者：
Kirschmeier, P
中科院分区：
文献类型：
--
作者：
Basso, AD;Mirza, A;Kirschmeier, P
Lonafarnib(SCH66336)是一种法尼基转移酶抑制剂(FTI)，可抑制H-RAS和其他法尼化蛋白的翻译后脂质修饰。K-和N-RAS也是法尼基转移酶的底物；然而，在FTIs处理后，它们被香叶基香叶基转移酶-1交替地进行异丙烯基化。尽管未能消除K-和N-RAS的前烯基化，但在临床前模型中，许多肿瘤的生长都受到FTI的抑制。这表明FTI的抗增殖作用依赖于阻断其他蛋白质的法尼化。Rheb(大脑中富含的RAS同源)是一种法尼化的小GTP酶，它积极地调节mTOR(哺乳动物雷帕霉素的靶标)信号。我们发现Rheb和Rheb2mRNA在不同肿瘤细胞系中相对正常细胞都有上调。来源于人Rheb和Rheb2羧基末端的多肽是法尼基转移酶的体外底物，而不是香叶基香叶基转移酶-1。SCH66336可完全抑制细胞培养中RHEB的苯丙基化，提示缺乏选择性的苯丙基化。SCH66336处理也抑制了S6核糖体蛋白的磷酸化，S6核糖体蛋白是Rheb和mTOR信号的下游靶。SCH66336不抑制表达Rheb-CSVL的细胞中S6的磷酸化，Rheb-CSVL是被设计为香叶化的Rheb的突变结构。重要的是，Rheb-CSVL的表达也分别阻断了SCH66336对他莫昔芬和多西紫杉醇诱导的MCF-7乳腺癌细胞和ES-2卵巢癌细胞的诱导凋亡。此外，雷帕霉素、小干扰RNA或显性阴性Rheb抑制Rheb信号转导增强了他莫昔芬和多西紫杉醇诱导的细胞凋亡，与FTI处理相似。这些研究表明，Rheb是通过法尼化修饰的，不是交替预烯基化的底物，并且在SCH66336增强对其他化疗药物的抗肿瘤反应中发挥作用。
Lonafarnib (SCH66336) is a farnesyl transferase inhibitor (FTI) that inhibits the post-translational lipid modification of H-Ras and other farnesylated proteins. K- and N-Ras are also substrates of farnesyl transferase; however, upon treatment with FTIs, they are alternatively prenylated by geranylgeranyl transferase-1. Despite the failure to abrogate prenylation of K- and N-Ras, growth of many tumors in preclinical models is inhibited by FTIs. This suggests that the anti-proliferative action of FTIs is dependent on blocking the farnesylation of other proteins. Rheb (Ras homologue enriched in brain) is a farnesylated small GTPase that positively regulates mTOR ( mammalian target of rapamycin) signaling. We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells. Peptides derived from the carboxyl termini of human Rheb and Rheb2 are in vitro substrates for farnesyl transferase but not geranylgeranyl transferase-1. Rheb prenylation in cell culture was completely inhibited by SCH66336, indicating a lack of alternative prenylation. SCH66336 treatment also inhibited the phosphorylation of S6 ribosomal protein, a downstream target of Rheb and mTOR signaling. SCH66336 did not inhibit S6 phosphorylation in cells expressing Rheb-CSVL, a mutant construct of Rheb designed to be geranylgeranylated. Importantly, expression of Rheb-CSVL also abrogated SCH66336 enhancement of tamoxifen-and docetaxel-induced apoptosis in MCF-7 breast cancer cells and ES-2 ovarian cancer cells, respectively. Further, inhibition of Rheb signaling by rapamycin treatment, small interfering RNA, or dominant negative Rheb enhanced tamoxifen- and docetaxel-induced apoptosis, similar to FTI treatment. These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336 enhancement of the antitumor response to other chemotherapeutics.