Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA 17033.
Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA 17033.
Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2317846121. doi: 10.1073/pnas.2317846121. Epub 2024 Nov 4.
From tumorigenesis to advanced metastatic stages, tumor cells encounter stress, ranging from limited nutrient and oxygen supply within the tumor microenvironment to extrinsic and intrinsic oxidative stress. Thus, tumor cells seize regulatory pathways to rapidly adapt to distinct physiologic conditions to promote cellular survival, including manipulation of mRNA translation. While it is now well established that metastatic tumor cells must up-regulate their antioxidant capacity to effectively spread and that regulation of antioxidant enzymes is imperative to disease progression, relatively few studies have assessed how translation and the hijacking of RNA systems contribute to antioxidant responses of tumors. Here, we review the major stress signaling pathways involved in translational regulation and discuss how these are affected by oxidative stress to promote prosurvival changes that manipulate antioxidant enzyme expression. We describe how tumors elicit these adaptive responses and detail how stress-induced translation can be regulated by kinases, RNA-binding proteins, RNA species, and RNA modification systems. We also highlight opportunities for further studies focused on the role of mRNA translation and RNA systems in the regulation of antioxidant enzyme expression, which may be of particular importance in the context of metastatic progression and therapeutic resistance.
从肿瘤发生到晚期转移阶段，肿瘤细胞会遇到各种压力，包括肿瘤微环境中有限的营养和氧气供应、外在和内在的氧化应激。因此，肿瘤细胞会抓住调节途径，迅速适应不同的生理条件，以促进细胞存活，包括操纵 mRNA 翻译。虽然现在已经很清楚，转移性肿瘤细胞必须上调其抗氧化能力才能有效地扩散，并且调节抗氧化酶对于疾病进展至关重要，但相对较少的研究评估了翻译和 RNA 系统的劫持如何有助于肿瘤的抗氧化反应。在这里，我们回顾了参与翻译调节的主要应激信号通路，并讨论了这些信号通路如何受到氧化应激的影响，以促进操纵抗氧化酶表达的生存促进变化。我们描述了肿瘤如何引发这些适应性反应，并详细说明了应激诱导的翻译如何受到激酶、RNA 结合蛋白、RNA 种类和 RNA 修饰系统的调节。我们还强调了进一步研究的机会，重点关注 mRNA 翻译和 RNA 系统在调节抗氧化酶表达中的作用，这在转移性进展和治疗抵抗的背景下可能尤为重要。
