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The impact of oncogenic RAS on redox balance and implications for cancer development.
Cell Death & Disease ( IF 9 ) Pub Date : 2019-12-18 , DOI: 10.1038/s41419-019-2192-y
Jonathan K M Lim 1 , Gabriel Leprivier 1
Affiliation  

The RAS family of proto-oncogenes comprises HRAS, KRAS, and NRAS, which are among the most mutated genes in human cancers. The RAS family genes encode small GTPases that coordinate key signaling pathways in response to growth factors. Mutations in RAS result in a constitutively active form of the protein that supports cellular transformation and tumorigenesis. The mechanisms of oncogenic RAS-mediated transformation encompass uncontrolled proliferation and inhibition of cell death through overactivation of the RAF-MEK-ERK and the PI3K-AKT pathways, respectively. In addition, the control of redox balance by RAS has also been proposed to play a role in its oncogenic properties. However, the exact role of redox balance in mediating mutant RAS transformation is still under debate. Here, we present, on one hand, the involvement of pro-oxidant components in oncogenic RAS transformation, such as NADPH oxidases and mitochondrial reactive oxygen species, and how these promote transformation. On the other hand, we describe the contribution of antioxidant components to mutant RAS transformation, including Nrf2, glutathione biosynthesis and xCT, as well as the mechanisms by which antioxidant programs drive transformation. Finally, we aim to reconcile the seemingly opposite effects of oncogenic RAS on redox balance and discuss a model for the complementary role of both pro-oxidant and antioxidant pathways in mutant RAS-driven tumor progression.

中文翻译:

致癌RAS对氧化还原平衡的影响及其对癌症发展的影响。

RAS原癌基因家族包括HRAS,KRAS和NRAS,它们是人类癌症中突变最多的基因之一。RAS家族基因编码小的GTP酶,这些GTP酶响应生长因子而协调关键的信号通路。RAS中的突变导致该蛋白的组成型活性形式支持细胞转化和肿瘤发生。致癌性RAS介导的转化机制包括不受控制的增殖和通过RAF-MEK-ERK和PI3K-AKT途径的过度活化来抑制细胞死亡。另外,还提出了通过RAS控制氧化还原平衡在其致癌性质中起作用。然而,氧化还原平衡在介导突变体RAS转化中的确切作用仍在争论中。在这里,我们一方面提出,促氧化剂成分参与致癌RAS转化的过程,例如NADPH氧化酶和线粒体活性氧种类,以及这些成分如何促进转化。另一方面,我们描述了抗氧化剂成分对突变RAS转化的贡献,包括Nrf2,谷胱甘肽生物合成和xCT,以及抗氧化剂程序驱动转化的机制。最后,我们旨在调和致癌RAS对氧化还原平衡的看似相反的作用,并讨论了促氧化剂和抗氧化剂途径在突变RAS驱动的肿瘤进展中的互补作用的模型。我们描述了抗氧化剂成分对突变RAS转化的贡献,包括Nrf2,谷胱甘肽生物合成和xCT,以及抗氧化剂程序驱动转化的机制。最后,我们旨在调和致癌RAS对氧化还原平衡的看似相反的作用,并讨论了促氧化剂和抗氧化剂途径在突变RAS驱动的肿瘤进展中的互补作用的模型。我们描述了抗氧化剂成分对突变RAS转化的贡献,包括Nrf2,谷胱甘肽生物合成和xCT,以及抗氧化剂程序驱动转化的机制。最后,我们旨在调和致癌RAS对氧化还原平衡的看似相反的作用,并讨论了促氧化剂和抗氧化剂途径在突变RAS驱动的肿瘤进展中的互补作用的模型。
更新日期:2019-12-19
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