oa Editorial [Hot Topic: The Therapeutic Potential of FOXO Proteins (Guest Editor: Wolfgang Link)]

New therapeutic strategies that focus on disease-relevant molecular events and interfere with specific signaling pathways have raised considerable expectations for the treatment of many human diseases. Forkhead box O (FOXO) proteins are emerging as transcriptional integrators of pathways that regulate a variety of cellular processes and have been considered as potential therapeutic targets for a broad range of human health conditions, including obesity, diabetes, hypertriglyceridemia, aging, infertility, muscle atrophy, inflammation, immune diseases and cancer [1] (see reviews in this issue). The four members of the mammalian Foxo family of proteins_Foxo1, Foxo3a, Foxo4 and Foxo6_belong to class O of the forkhead/winged helix transcription factors (Fox) and function as transcriptional regulators in the cell nucleus [2]. Foxo proteins influence the transcription of an ever-growing list of target genes through direct binding to their consensus DNA sequence or via protein-protein interactions with other transcription factors and coactivators [3]. Foxo factors are ancient, evolutionarily conserved targets of insulin-like signaling and have evolved to respond to multiple intracellular and extracellular stimuli with engagement of adaptive gene expression programs. The activity of Foxo factors is regulated by a sophisticated signaling network that integrates metabolic, mitogenic and stress signals resulting in a specific pattern of posttranscriptional modifications. Phosphorylation, acetylation, methylation, glycosylation and ubiquitination modulate FoxO function and control nuclearcytoplasmic shuttling, DNA binding and protein-protein interactions. Foxo proteins have been recently established as bona fide tumor suppressors and correspondingly the abrogation of Foxo function is a key feature of many tumor cells. Contrary to other tumor suppressors like p53 or PTEN whose functions are abrogated via genetic or epigenetic changes, inactivation of FOXOs occurs mostly due to posttranscriptional up-regulation of their inhibitory inputs. That offers a wide range of possibilities for restoring FOXO activity e.g. with small molecule inhibitors targeting up-regulated FOXO repressors [4-6]. However, as Foxo factors regulate a broad variety of cellular functions some of which are seemingly opposing such as apoptosis and resistance against oxidative stress, their therapeutic activation or inhibition may lead to undesirable clinical outcome. Therapeutic interference with FOXO functions might have both beneficial effects in one disease setting while having deleterious effects in another. A number of potential therapeutic limitations could arise particularly from chronic modulation of FOXO function. Selective inhibition of FOXO1 activity in the liver might ameliorate metabolic abnormalities associated with obesity and diabetes, while at the same time promote hepatic fibrosis (see Kim et al., this issue [7]). Therapies aimed at reactivating FOXO activity could provide exciting opportunities for innovative treatments for cancer patients [8]. Accordingly, the cytostatic and cytotoxic effects of a diverse spectrum of anti-cancer drugs are mediated through the activation of FOXO factors. Paradoxically, FOXO proteins also contribute to drug resistance by driving the expression of genes important for drug efflux as well as DNA repair and cell survival pathways in drug resistant cancers (see Wilson et al., this issue). In addition, while FOXO proteins exert many if not all the properties attributed to tumor suppressors they may promote the maintenance of the very few tumor-initiating cells that regenerate the disease [9, 10] (see Ghaffari et al., this issue). Based on our current knowledge on the regulation and functions of FOXO proteins the success of their exploitation in the clinic critically relies on the capability to engage specific FOXO-dependent transcriptional programs. The development of therapeutic agents, drug combinations and treatment regimes that modulate specific subsets of FOXO target genes at the right place at the right time constitute a major challenge for basic and drug discovery research. In this special issue of CDT leading experts in the field discuss controversies and advances in our understanding of FOXO biology and its biomedical applications. Huarui Lu and Haojie Huang focus on the therapeutic potential of the FOXO family member FOXO1 for the treatment of diseases such as cancer, diabetes and muscular atrophy. Although Foxo1 null mice exhibit embryonic lethal phenotypes with marked evidence of vascular defects precluding the analysis of the role of this isoform in adult tissues several genetically modified mouse models have been developed that shed light on the role of FOXO1 in human diseases. Dae Hyun Kim, Ting Zhang, Steven Ringquist and H. Henry Dong discuss the hypothesis that selective inhibition of FOXO1 in the liver would ameliorate hypertriglyceridemia, a common lipid disorder associated with obesity and type 2 diabetis and a hallmark of metabolic syndrome. Miranda S. C. Wilson, Jan J. Brosens, Helma D. C. Schwenen and Eric W.-F. Lam review evidence indicating that targeting the FOXO-FOXM1 axis could be a viable strategy for treatment of cancer and for overcoming drug resistance. Saghi Ghaffari, Safak Yalcin, Maite Rielland and Xin Zhang describe the critical relationship between the FOXO driven detoxification of reactive oxygen species (ROS) and the regulation of quiescence in stem cell populations including tumorinitiating cells and explore the therapeutic implications.....