The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Oncogene. 2010 Jul 8;29(27):3881-95. doi: 10.1038/onc.2010.153. Epub 2010 May 10.
To proliferate and expand in an environment with limited nutrients, cancer cells co-opt cellular regulatory pathways that facilitate adaptation and thereby maintain tumor growth and survival potential. The endoplasmic reticulum (ER) is uniquely positioned to sense nutrient deprivation stress and subsequently engage signaling pathways that promote adaptive strategies. As such, components of the ER stress-signaling pathway represent potential antineoplastic targets. However, recent investigations into the role of the ER resident protein kinase, RNA-dependent protein kinase (PKR)-like ER kinase (PERK) have paradoxically suggested both pro- and anti-tumorigenic properties. We have used animal models of mammary carcinoma to interrogate the contribution of PERK in the neoplastic process. The ablation of PERK in tumor cells resulted in impaired regeneration of intracellular antioxidants and accumulation of reactive oxygen species triggering oxidative DNA damage. Ultimately, PERK deficiency impeded progression through the cell cycle because of the activation of the DNA damage checkpoint. Our data reveal that PERK-dependent signaling is used during both tumor initiation and expansion to maintain redox homeostasis, thereby facilitating tumor growth.
为了在营养有限的环境中增殖和扩张，癌细胞会借用细胞调节途径，从而适应并维持肿瘤生长和存活的潜力。内质网（ER）是唯一能够感知营养剥夺应激的细胞器，并随后参与促进适应性策略的信号通路。因此，内质网应激信号通路的组成部分代表了潜在的抗肿瘤靶点。然而，最近对 ER 驻留蛋白激酶 RNA 依赖性蛋白激酶（PKR）样 ER 激酶（PERK）的作用的研究表明，PERK 具有促肿瘤和抗肿瘤双重特性。我们使用乳腺癌动物模型来研究 PERK 在肿瘤发生过程中的作用。PERK 在肿瘤细胞中的缺失导致细胞内抗氧化剂的再生受损，活性氧的积累触发氧化 DNA 损伤。最终，由于 DNA 损伤检查点的激活，PERK 缺陷阻碍了细胞周期的进展。我们的数据表明，PERK 依赖性信号通路在肿瘤起始和扩张过程中被用来维持氧化还原平衡，从而促进肿瘤生长。
