文章：

异构酶PIN1控制着许多癌症驱动途径，是一个独特的药物靶点

The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target

原文发布日期：2016-06-03

DOI: 10.1038/nrc.2016.49

类型: Review Article

开放获取: 否

要点：

1. In contrast to all other known prolyl isomerases, PIN1 has the unique property of binding to and catalysing the conversion of specific proline-directed serine/threonine phosphorylation motifs between the two distinct cis and trans conformations of proline. Such PIN1-catalysed prolyl isomerization functions as a molecular timer that modulates many targets at various steps of a given cellular process to synchronously control the amplitude and duration of a given cellular response or process.
2. PIN1 is tightly regulated under physiological conditions, but is commonly overexpressed and/or overactivated in most human cancers, with its levels being correlated with clinical outcome in many cancers. By contrast, PIN1 polymorphisms that lower PIN1 expression are associated with reduced risk for multiple cancers.
3. Pin1-null mice, which develop normally, are highly resistant to tumorigenesis even after overexpression of oncogenes or ablation of tumour suppressors. Conversely, PIN1 overexpression disrupts cell cycle coordination and leads to chromosome instability and tumorigenesis.
4. Abnormal PIN1 activation disrupts the balance in cancer to activate at least 40 oncogenes and inactivate at least 20 tumour suppressors, many of which have a known role in cancer stem cells (CSCs).
5. PIN1 inhibitors have the promising and desirable property of restoring the balance in cancer by simultaneously blocking many cancer-driving pathways in cancer cells and CSCs for treating aggressive and drug-resistant cancers. PIN1 is a major target of the drug all-trans retinoic acid (ATRA) in acute promyelocytic leukaemia.
6. The recent development of cis and trans conformation-specific antibodies provides direct evidence for conformation-specific function and regulation by PIN1, and should facilitate the discovery of novel disease mechanisms and potential new therapies for PIN1-related diseases. Further development of conformation-specific antibodies against oncogenes and tumour suppressors that are PIN1 substrates would provide powerful tools for studying cancer signalling and may lead to new cancer diagnostics and/or therapeutics.

要点翻译：

1. 与其他所有已知的脯氨酰异构酶不同，PIN1具有独特特性：它能特异性结合脯氨酸导向的丝氨酸/苏氨酸磷酸化基序，并催化其脯氨酸残基在顺式和反式两种构型间转化。这种PIN1催化的脯氨酰异构化作用如同分子计时器，通过在特定细胞进程的不同步骤调控多种靶标，同步控制细胞应答或过程的强度与持续时间。
2. 在生理条件下，PIN1受到严格调控，但在大多数人类癌症中常出现过表达和/或过度活化，其表达水平与多种癌症的临床预后相关。相反，降低PIN1表达的多态性则与多种癌症风险下降相关。
3. 发育正常的Pin1基因敲除小鼠即使过表达癌基因或剔除抑癌基因后，仍表现出极强的抗肿瘤生成能力。反之，PIN1过表达会破坏细胞周期协调性，导致染色体不稳定和肿瘤发生。
4. 异常的PIN1活化会破坏癌症中的平衡状态，激活至少40种癌基因并灭活至少20种抑癌基因，其中许多在癌症干细胞中具有已知作用。
5. PIN1抑制剂具备理想特性，能通过同步阻断癌细胞和癌症干细胞中多条致癌通路来恢复癌症中的平衡，为治疗侵袭性和耐药性癌症带来希望。PIN1是全反式维甲酸治疗急性早幼粒细胞白血病的重要作用靶点。
6. 近期开发的构象特异性抗体为PIN1介导的构象特异性功能与调控提供了直接证据，这将促进对PIN1相关疾病新型机制的发现和潜在疗法的开发。针对PIN1底物（癌基因和抑癌基因）进一步开发构象特异性抗体，将为癌症信号转导研究提供强大工具，并可能催生新的癌症诊断和治疗方法。

英文摘要：

Targeted drugs have changed cancer treatment but are often ineffective in the long term against solid tumours, largely because of the activation of heterogeneous oncogenic pathways. A central common signalling mechanism in many of these pathways is proline-directed phosphorylation, which is regulated by many kinases and phosphatases. The structure and function of these phosphorylated proteins are further controlled by a single proline isomerase: PIN1. PIN1 is overactivated in cancers and it promotes cancer and cancer stem cells by disrupting the balance of oncogenes and tumour suppressors. This Review discusses the roles of PIN1 in cancer and the potential of PIN1 inhibitors to restore this balance.

摘要翻译： 

靶向药物改变了癌症治疗，但在实体瘤的长期疗效上常显不足，主要原因在于异质性致癌通路的激活。这些通路中一个核心的共同信号机制是脯氨酸导向的磷酸化，其受多种激酶和磷酸酶调控。磷酸化蛋白的结构与功能进一步由单一脯氨酸异构酶PIN1掌控。PIN1在癌症中过度激活，通过破坏癌基因与抑癌基因的平衡，促进肿瘤及癌症干细胞的形成。本文综述了PIN1在癌症中的作用，并探讨了PIN1抑制剂恢复这一平衡的潜力。

原文链接：

The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target