OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins

Abstract

Forkhead transcription factors have a 'winged helix' domain and regulate processes that range from cell longevity to cell death. Of the mammalian forkhead family members in the O class, FoxO1, FoxO3a and FoxO4 can fill a crucial void for the treatment of disorders that include aging, cancer, diabetes, infertility, neurodegeneration and immune system dysfunction. Yet, observations that forkhead family members also can compromise clinical utility have fueled controversy and highlight the necessity to further outline the integrated cellular pathways governed by these transcription factors. Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.

Figure 1

FoxO proteins are integrated in multiple signal transduction pathways that govern cell longevity, metabolism, survival and tumorigenesis. During stimuli such as oxidative stress, FoxO can be linked to several pathways that directly modulate FoxO activity and its phosphorylation status (p-FoxO), such as by protein kinase B (Akt), or that require FoxO to ultimately determine several cellular processes such as cell cycle regulation, apoptotic injury and malignancy. These interconnected pathways involve IκB kinase (IKK), IκB, protein 14–3-3, growth-arrest and DNA-damage-response protein 45 (Gadd45), Fas ligand (Fas L), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the BH3-only proteins Noxa and Bim, p53, c-myc, p27, mitochondrial membrane potential (Mito), cytochrome c (Cyto-c) and caspases.