Transcriptional role of FOXO1 in drug resistance through antioxidant defense systems

Abstract

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.