Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute London, UK.
Front Oncol. 2013 Apr 25;3:96. doi: 10.3389/fonc.2013.00096. eCollection 2013.
Alterations in cellular metabolism are a key feature of the transformed phenotype. Enhanced macromolecule synthesis is a prerequisite for rapid proliferation but may also contribute to induction of angiogenesis, metastasis formation, and tumor progression, thereby leading to a poorer clinical outcome. Metabolic adaptations enable cancer cells to survive in suboptimal growth conditions, such as the limited supply of nutrient and oxygen often found in the tumor microenvironment. Metabolic changes, including activation of glycolysis and inhibition of mitochondrial ATP production, are induced under hypoxia to promote survival in low oxygen. FOXO3a, a transcription factor that is inhibited by the phosphatidylinositol 3-kinase/Akt pathway and is upregulated in hypoxia, has emerged as an important negative regulator of MYC function. Recent studies have revealed that FOXO3a acts as a negative regulator of mitochondrial function through inhibition of MYC. Ablation of FOXO3a prevents the inhibition of mitochondrial function induced by hypoxia and results in enhanced oxidative stress. This review will focus on the antagonism between FOXO3a and MYC and discuss their role in cellular bioenergetics, reactive oxygen metabolism, and adaptation to hypoxia, raising questions about the role of FOXO proteins in cancer.
细胞代谢的改变是转化表型的一个关键特征。增强大分子合成是快速增殖的前提，但也可能有助于诱导血管生成、转移形成和肿瘤进展，从而导致更差的临床结果。代谢适应使癌细胞能够在营养和氧气供应有限等不利生长条件下存活，这种情况在肿瘤微环境中经常出现。在缺氧条件下会诱导代谢变化，包括糖酵解的激活和线粒体 ATP 产生的抑制，以促进在低氧环境下的存活。FOXO3a 是一种转录因子，它被磷酸肌醇 3-激酶/ Akt 途径抑制，在缺氧条件下上调，已成为 MYC 功能的重要负调控因子。最近的研究表明，FOXO3a 通过抑制 MYC 来作为线粒体功能的负调控因子。FOXO3a 的缺失可防止缺氧诱导的线粒体功能抑制，并导致氧化应激增强。这篇综述将重点讨论 FOXO3a 和 MYC 之间的拮抗作用，并讨论它们在细胞生物能量学、活性氧代谢和对缺氧的适应中的作用，提出关于 FOXO 蛋白在癌症中的作用的问题。
