Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Curr Drug Targets. 2011 Aug;12(9):1284-90. doi: 10.2174/138945011796150299.
Forkhead O transcription factors (FOXO) are critical for the regulation of cell cycle arrest, cell death, and DNA damage repair. Inactivation of FOXO proteins may be associated with tumorigenesis, including breast cancer, prostate cancer, glioblastoma, rhabdomyosarcoma, and leukemia. Accumulated evidence shows that activation of oncogenic pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase suppresses FOXO transcriptional activity through the phosphorylation of FOXOs at different sites that ultimately leads to nuclear exclusion and degradation of FOXOs. In addition, posttranslational modifications of FOXOs such as acetylation, methylation and ubiquitination also contribute to modulating FOXO3a functions. Several anti-cancer drugs like paclitaxel, imatinib, and doxorubicin activate FOXO3a by counteracting those oncogenic pathways which restrain FOXOs functions. In this review, we will illustrate the regulation of FOXOs and reveal potential therapeutics that target FOXOs for cancer treatment.
叉头框转录因子（FOXO）在细胞周期停滞、细胞死亡和 DNA 损伤修复的调控中起着关键作用。FOXO 蛋白的失活可能与肿瘤发生有关，包括乳腺癌、前列腺癌、胶质母细胞瘤、横纹肌肉瘤和白血病。大量证据表明，磷酸肌醇 3-激酶/AKT/IKK 或 RAS/丝裂原活化蛋白激酶等致癌途径的激活通过在 FOXO 的不同位点磷酸化来抑制 FOXO 的转录活性，最终导致 FOXO 的核排除和降解。此外，FOXO 的翻译后修饰，如乙酰化、甲基化和泛素化，也有助于调节 FOXO3a 的功能。几种抗癌药物，如紫杉醇、伊马替尼和多柔比星，通过对抗那些抑制 FOXO 功能的致癌途径来激活 FOXO3a。在这篇综述中，我们将阐述 FOXO 的调控，并揭示针对 FOXO 的潜在治疗方法，以用于癌症治疗。
