Department of Obstetrics and Gynecology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
Adv Exp Med Biol. 2009;665:171-9. doi: 10.1007/978-1-4419-1599-3_13.
FOXO transcription factors promote cell cycle arrest, apoptosis, DNA damage repair and detoxification of reactive oxygen species by regulating specific gene setting. As FOXO possess diverse functions, which partly seemed opposing, the multiple mechanisms, including transcriptional activity and subcellular localization, are differentially regulated according to various types or intensities of cellular stress responses. Since FOXO transcription factors are critical mediators ofapoptosis in cytotoxicityinducing drugs, its involvement in the development of drug resistance is an important issue in cancer therapy. Indeed, FOXO1 expression was distinctively upregulated in paclitaxel resistant cell line and enhanced by exposure to paclitaxel with subcellular translocation. In addition, FOXO1 overexpression, predominantly in cytosol, was frequently observed in cancer tissue samples from chemoresistant patients compared to chemosensitive patients. FOXO1 silencing in paclitaxel resistant cell line decreased its resistance through modulation of downstream targets of FOXO1 involving oxidative stress. Alteration of oxidative stress by cotreatment with pharmacologic modulators of reactive oxygen species also attenuated cytotoxicity of paclitaxel. Furthermore, FOXO1 silencing attenuated intracellular reactive oxygen species levels, which collectively suggest one of possible explanations in transcriptional role of FOXO1 as redox mechanism leading to drug resistance through its downstream target involving defence mechanism against oxidative stress.
叉头框转录因子通过调节特定的基因表达来促进细胞周期停滞、细胞凋亡、DNA 损伤修复和活性氧解毒。由于 FOXO 具有多种功能，这些功能部分似乎相互矛盾，因此根据不同类型或强度的细胞应激反应，多种机制（包括转录活性和亚细胞定位）会被差异化调节。由于 FOXO 转录因子是细胞毒性诱导药物中细胞凋亡的关键介质，其参与耐药性的发展是癌症治疗中的一个重要问题。事实上，在紫杉醇耐药细胞系中，FOXO1 的表达明显上调，并通过暴露于紫杉醇中亚细胞易位而增强。此外，与化疗敏感患者相比，在化疗耐药患者的癌症组织样本中，FOXO1 过表达（主要在细胞质中）更为常见。在紫杉醇耐药细胞系中沉默 FOXO1 通过调节 FOXO1 的下游靶标（涉及氧化应激）降低其耐药性。用活性氧的药理学调节剂共同处理改变氧化应激也会减弱紫杉醇的细胞毒性。此外，沉默 FOXO1 可降低细胞内活性氧水平，这表明 FOXO1 的转录作用可能是一种解释，即通过其涉及抗氧化应激防御机制的下游靶标，作为氧化还原机制导致耐药性。
