文章：

癌症中通过mTOR的缺氧信号传导和未折叠蛋白反应

Hypoxia signalling through mTOR and the unfolded protein response in cancer

原文发布日期：2008-10-10

DOI: 10.1038/nrc2501

类型: Review Article

开放获取: 否

要点：

1. Cellular responses to hypoxia are mediated by both hypoxia-inducible factor (HIF)-dependent and HIF-independent pathways. Each of these O₂-sensitive signalling pathways exhibits unique sensitivity to the severity and duration of O₂ deprivation.
2. Hypoxia inhibits signalling downstream of the kinase mammalian target of rapamycin (mTOR) and mRNA translation initiation through multiple independent mechanisms. Signalling through this pathway appears to influence both tumour progression and hypoxia tolerance in advanced tumours.
3. Severe hypoxic exposure causes endoplasmic reticulum (ER) stress and leads to rapid activation of the unfolded protein response (UPR). The UPR regulates several downstream effector pathways that together function to promote hypoxia tolerance.
4. Hypoxic signalling through mTOR and the UPR results in significant changes in mRNA translation that influence gene expression and cellular behaviour in hypoxic cells. Targeting these pathways can reduce or slow tumour growth.
5. Many of the cellular consequences of hypoxia are jointly influenced by overlapping O₂-sensitive pathways. HIF, mTOR and UPR signalling during hypoxia influence tumour metabolism, autophagy and ER homeostasis.
6. Many current and experimental anticancer agents cause ER stress and activate the UPR, and may thus show selective toxicity to hypoxic cells. Conversely, hypoxic signalling through the mTOR pathway is likely to influence the efficacy of many of the new drugs targeting this pathway.

要点翻译：

1. 细胞对缺氧的反应由缺氧诱导因子（HIF）依赖性和非HIF依赖性通路共同介导。这些氧敏感信号通路对缺氧严重程度和持续时间均表现出独特的敏感性。
2. 缺氧通过多种独立机制抑制雷帕霉素哺乳动物靶标（mTOR）激酶下游信号传导及mRNA翻译起始。该通路信号似乎同时影响肿瘤进展和晚期肿瘤的缺氧耐受能力。
3. 严重缺氧暴露会引起内质网（ER）应激，并迅速激活未折叠蛋白反应（UPR）。UPR调控若干下游效应通路，这些通路共同作用以促进缺氧耐受性。
4. 通过mTOR和UPR的缺氧信号传导导致mRNA翻译发生显著变化，进而影响缺氧细胞的基因表达和细胞行为。靶向这些通路可减缓或抑制肿瘤生长。
5. 缺氧的多数细胞效应受到重叠的氧敏感通路共同影响。缺氧条件下的HIF、mTOR和UPR信号传导共同调控肿瘤代谢、自噬及内质网稳态。
6. 许多现有及实验性抗癌药物会引发内质网应激并激活UPR，因此可能对缺氧细胞表现出选择性毒性。相反，通过mTOR通路的缺氧信号传导可能会影响针对该通路的新药疗效。

英文摘要：

Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O2-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.

摘要翻译： 

大多数肿瘤中都会发生缺氧，促进血管生成、转移和治疗的耐药性。缺氧反应部分通过缺氧诱导因子家族转录因子（HIFs）的激活来调控。最近，另外两个对氧气敏感的信号通路也被牵涉其中：通过雷帕霉素靶蛋白（mTOR）激酶的信号传导，以及通过未折叠蛋白反应（UPR）激活的信号传导。尽管它们被独立激活，但越来越多的证据表明，HIF依赖、mTOR依赖和UPR依赖的缺氧反应是以一种整合的方式发挥作用的，彼此影响，并共同作用于下游通路，从而影响基因表达、代谢、细胞存活、肿瘤发生及肿瘤生长。

原文链接：

Hypoxia signalling through mTOR and the unfolded protein response in cancer