Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Curr Top Dev Biol. 2018;127:49-103. doi: 10.1016/bs.ctdb.2017.10.003. Epub 2018 Jan 5.
A paradigm shift is emerging within the FOXO field and accumulating evidence indicates that we need to reappreciate the role of FOXOs, at least in cancer development. Here, we discuss the possibility that FOXOs are both tumor suppressors as well as promoters of tumor progression. This is mostly dependent on the biological context. Critical to this dichotomous role is the notion that FOXOs are central in preserving cellular homeostasis in redox control, genomic stability, and protein turnover. From this perspective, a paradoxical role in both suppressing and enhancing tumor progression can be reconciled. As many small molecules targeting the PI3K pathway are developed by big pharmaceutical companies and/or are in clinical trial, we will discuss what the consequences may be for the context-dependent role of FOXOs in tumor development in treatment options based on active PI3K signaling in tumors.
FOXO 领域正在出现范式转变，越来越多的证据表明，我们需要重新认识 FOXO 的作用，至少在癌症发展方面是这样。在这里，我们讨论了 FOXO 既是肿瘤抑制因子，也是肿瘤进展促进因子的可能性。这主要取决于生物学背景。对于这种双重作用至关重要的是这样一种观点，即 FOXO 在维持细胞内稳态、氧化还原控制、基因组稳定性和蛋白质周转方面发挥着核心作用。从这个角度来看，FOXO 在抑制和促进肿瘤进展方面的矛盾作用可以得到协调。由于许多针对 PI3K 通路的小分子药物都是由大型制药公司开发的，或者正在临床试验中，我们将讨论在基于肿瘤中活跃的 PI3K 信号的治疗选择中，FOXO 在肿瘤发展中的这种依赖于背景的作用可能会产生什么后果。
