文章：

靶向蛋白烯酰化用于癌症治疗

Targeting protein prenylation for cancer therapy

原文发布日期：2011-10-24

DOI: 10.1038/nrc3151

类型: Review Article

开放获取: 否

要点：

1. Post-translational modifications with the lipids farnesyl or geranylgeranyl (together referred to as prenyl) are catalysed by farnesyltransferase (FT) or geranylgeranyltransferase 1 (GGT1) and are required for the cellular localization, function and cancer-causing activities of some proteins. Among the hundreds of proteins that are estimated to be prenylated most are either exclusively farnesylated (for example, HRAS and RAS homologue enriched in brain (RHEB)) or geranylgeranylated (for example, RHOA, RHOC, RALA and RALB); some are both farnesylated and geranylgeranylated (RHOB), and others are naturally farnesylated but become geranylgeranylated when FT is inhibited (for example, KRAS and NRAS).
2. These and other important observations prompted the design and development of inhibitors of FT (FTIs) and GGT1 (GGTIs) as potential anticancer drugs. Several FTIs have been tested clinically but only one GGTI has recently entered clinical trials.
3. Further validation of FT and GGT1 as anticancer drug targets was recently provided by genetic mouse models: conditional loss of FT and/or GGT1 hampers mutant KRAS-induced tumorigenesis and extends the lifespan of mice.
4. FTI treatment results in the reversal of several hallmarks of cancer, including mitotic arrest at prometaphase, induction of apoptosis, inhibition of anchorage-dependent and anchorage-independent growth, invasion, angiogenesis and tumour growth, as well as induction of tumour regression in animal models. These effects seem to be mediated by interference with aberrant signal transduction pathways such as RAF–MEK–ERK, PI3K–AKT, and other oncogenic and survival pathways.
5. GGTI treatment also results in the reversal of the cancer hallmarks mentioned above except that they block cells in the G1 phase of the cell cycle, and this seems to be owing to their ability to induce the accumulation of the cyclin-dependent kinase (CDK) inhibitors p21 and p27 and to inhibit CDKs and induce hypophosphorylation of RB. GGTI treatment also decreases the levels of phospho-AKT and survivin, and this seems to mediate their ability to induce apoptosis.
6. Although in preclinical models FTIs are highly effective as antitumour agents, in clinical trials limited efficacy was observed. This is primarily due to poor patient selection. This in turn is due to our lack of understanding of the mechanism of action of FTIs. In the future, a major effort must be dedicated to identifying the prenylated proteins the inhibition of which is responsible for the antitumour effects of PTIs. This will be of great value not only for enhancing our understanding of the mechanism of action of FTIs and GGTIs, but also for selecting patients whose tumours are addicted to specific prenylated proteins and who are more likely to respond to these agents. Recent advances in techniques to characterize the human prenylome are likely to accelerate achieving these crucial goals in the prenylation field.

要点翻译：

1. 由法尼基或香叶基香叶基（统称为异戊二烯基）进行的翻译后修饰，由法尼基转移酶（FT）或香叶基香叶基转移酶1（GGT1）催化，是一些蛋白质的细胞定位、功能和致癌活性所必需的。在估计存在的数百种异戊二烯化蛋白质中，大多数要么是仅被法尼基化（例如HRAS和脑内富集的RAS同源物RHEB），要么是仅被香叶基香叶基化（例如RHOA、RHOC、RALA和RALB）；有些则同时被法尼基化和香叶基香叶基化（如RHOB），还有一些在自然状态下是法尼基化的，但在FT被抑制时会转变为香叶基香叶基化（例如KRAS和NRAS）。
2. 这些以及其他重要观察结果促使人们设计和开发了FT抑制剂（FTIs）和GGT1抑制剂（GGTIs）作为潜在的抗癌药物。几种FTIs已在临床上进行了测试，但只有一种GGTI最近进入了临床试验。
3. 最近通过遗传小鼠模型进一步证实了FT和GGT1作为抗癌药物靶点的价值：条件性缺失FT和/或GGT1会阻碍突变KRAS诱导的肿瘤发生，并延长小鼠的寿命。
4. FTI治疗可导致多种癌症特征的逆转，包括前中期有丝分裂停滞、诱导凋亡、抑制锚定依赖性和非锚定性生长、侵袭、血管生成和肿瘤生长，以及在动物模型中诱导肿瘤消退。这些效应似乎是通过干扰异常的信号转导通路介导的，如RAF–MEK–ERK、PI3K–AKT以及其他致癌和生存通路。
5. GGTI治疗同样能逆转上述癌症特征，不同之处在于它们将细胞阻滞在细胞周期的G1期，这似乎是由于它们能够诱导细胞周期蛋白依赖性激酶（CDK）抑制剂p21和p27的积累，并抑制CDK和诱导RB的低磷酸化。GGTI治疗还会降低磷酸化AKT和生存素的水平，这似乎介导了其诱导凋亡的能力。
6. 尽管在临床前模型中FTIs作为抗肿瘤药物非常有效，但在临床试验中观察到的疗效有限。这主要是由于患者选择不当。而这又是因为我们对FTIs的作用机制缺乏了解。未来，必须致力于鉴定那些其抑制能产生PTIs抗肿瘤效应的异戊二烯化蛋白质。这不仅对增强我们对FTIs和GGTIs作用机制的理解具有重要价值，而且有助于选择那些肿瘤依赖于特定异戊二烯化蛋白质、因而更可能对这些药物产生反应的患者。在表征人类异戊二烯组技术方面的最新进展，可能会加速在异戊二烯化领域实现这些关键目标。

英文摘要：

Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyltransferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.

摘要翻译： 

蛋白法尼基化和香叶基香叶基化（合称为“异戊烯化”）是脂质翻译后修饰，对许多致癌蛋白（包括部分RAS家族成员）的转化活性至关重要。基于此，法尼基转移酶（FT）和香叶基香叶基转移酶1（GGT1）抑制剂被开发为潜在抗癌药物。本文综述FT与GGT1抑制剂（FTI和GGTI）如何影响信号转导通路、细胞周期进程、增殖及细胞存活。尽管临床前效果显著，仅少数患者对FTI有反应；识别依赖异戊烯化存活的肿瘤仍是难题，文中探讨应对策略。近期已有GGTI进入临床，其安全性与疗效尚待临床试验结果。

原文链接：

Targeting protein prenylation for cancer therapy