文章：

超越PTEN突变：PI3K通路作为肿瘤发生过程中多种输入的整合者

Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis

原文发布日期：2006-02-02

DOI: 10.1038/nrc1819

类型: Review Article

开放获取: 否

要点：

1. The phosphatidylinositol 3-kinase (PI3K)–phosphatase with tensin homology (PTEN) signalling pathway is one of the most commonly altered pathways in human tumours. However, mutations of the PTEN gene itself account for only a fraction of these molecular changes.
2. The PI3K–PTEN pathway promotes cell survival and proliferation, increases in cell size and chemoresistance. Each of these biological outcomes results from the interaction of this pathway with other signalling networks.
3. Ras and its downstream effectors can activate components of the PI3K–PTEN pathway through numerous mechanisms. Each mechanism might be restricted to a particular tumour type, allowing the design of a specific therapy that kills cancer cells but leaves normal tissue unharmed.
4. Crosstalk between the PI3K–PTEN and p53 pathways occurs at multiple nodes in these pathways. When both PTEN and p53 are inactivated by mutations, malignancy is promoted in a synergistic manner.
5. The Ras, PI3K–PTEN and p53 pathways all converge either directly or indirectly on the tumour suppressor TSC2, indicating a crucial role for this molecule in the integration of multiple signals.
6. DJ1 is a novel regulator of the PI3K–PTEN pathway and is associated with breast and lung cancers.
7. The multiple pathways that influence the PI3K–PTEN signalling network do so through a variety of mechanisms, providing numerous potential drug targets. Drugs that act on these targets could be formulated to work either synergistically with agents that act directly on PI3K or on elements that function downstream of mutated pathway components. These drugs might offer an attractive additional or alternative approach to combating PI3K-dependent tumours.

要点翻译：

1. 磷脂酰肌醇3-激酶（PI3K）-张力蛋白同源磷酸酶（PTEN）信号通路是人类肿瘤中最常发生改变的途径之一。然而PTEN基因本身的突变仅占这些分子变化的一部分。
2. PI3K-PTEN通路可促进细胞存活与增殖、增加细胞体积并诱导化疗耐药。这些生物学效应均源于该通路与其他信号网络的相互作用。
3. Ras及其下游效应器可通过多种机制激活PI3K-PTEN通路组分。每种机制可能仅限于特定肿瘤类型，这使得设计特异性疗法成为可能，即选择性杀伤癌细胞而不损伤正常组织。
4. PI3K-PTEN与p53通路在这些途径的多个节点存在交叉对话。当PTEN和p53同时因突变失活时，会以协同方式促进恶性肿瘤进展。
5. Ras、PI3K-PTEN和p53通路均直接或间接汇聚于抑癌因子TSC2，表明该分子在整合多重信号中起关键作用。
6. DJ1是PI3K-PTEN通路的新型调控因子，与乳腺癌和肺癌的发生相关。
7. 影响PI3K-PTEN信号网络的多种途径通过不同机制发挥作用，这为药物靶点开发提供了众多可能性。针对这些靶点的药物可与直接作用于PI3K的制剂协同使用，或作用于突变通路组分下游元件。这些药物可能为对抗PI3K依赖性肿瘤提供具有吸引力的补充或替代治疗策略。

英文摘要：

The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K). Although PTEN is mutated or deleted in many tumours, deregulation of the PI3K–PTEN network also occurs through other mechanisms. Crosstalk between the PI3K pathways and other tumorigenic signalling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation. How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?

摘要翻译： 

抑癌磷酸酶张力蛋白同源物（PTEN）是磷脂酰肌醇3-激酶（PI3K）启动的细胞存活信号通路中最重要的负调控因子。尽管PTEN在多种肿瘤中存在突变或缺失，PI3K-PTEN网络的失调也可通过其他机制发生。PI3K通路与涉及Ras、p53、TOR（雷帕霉素靶蛋白）或DJ1等其他致癌信号通路之间的交互作用，可能促成这种失调。PI3K通路如何整合来自众多来源的信号？这些信息又如何应用于癌症治疗的合理设计？

原文链接：

Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis