FOXO Signaling Pathways as Therapeutic Targets in Cancer

Abstract

Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers. During apoptosis, FOXOs are involved in mitochondria-dependent and -independent processes triggering the expression of death receptor ligands like Fas ligand, TNF apoptosis ligand and Bcl‑XL, bNIP3, Bim from Bcl-2 family members. Different types of growth factors like insulin play a vital role in the regulation of FOXOs. The most important pathway interacting with FOXO in different types of cancers is the PI3K/AKT pathway. Some other important pathways such as the Ras-MEK-ERK, IKK and AMPK pathways are also associated with FOXOs in tumorigenesis. Therapeutically targeting the FOXO signaling pathway(s) could lead to the discovery and development of efficacious agents against some cancers, but this requires an enhanced understanding and knowledge of FOXO transcription factors and their regulation and functioning. This review focused on the current understanding of cell biology of FOXO transcription factors which relates to their potential role as targets for the treatment and prevention of human cancers. We also discuss drugs which are currently being used for cancer treatment along with their target pathways and also point out some potential drawbacks of those drugs, which further signifies the need for development of new drug strategies in the field of cancer treatment.

Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells

“…The activation of Foxo and its proapoptotic properties is under regulation of multiple cell signaling (Farhan et al, ). The inhibitory phosphorylation Thr32 P‐Foxo3a was transiently upregulated at 6–12 hr, while dropped afterwards in sorafenib (10 µM)‐treated HepG2 cells (Figure g).…”

Microarray expression profile of long non‐coding RNAs in human lung adenocarcinoma

“…Our pathway analysis showed that aberrant mRNAs were enriched in processes closely related to other cancer biology that encompassed the FoxO signaling pathway. As a subfamily of the forkhead transcription factor family, Forkhead box O (FOXO) is crucial to cellular consequences, and is also considered a cancer suppressor in different malignancies . Wang et al .…”

Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss

“…All letters are capitalized for human Fox proteins. For the mouse, only the initial letter is listed as uppercase and for all other chordates the initial and subclass letters are in uppercase (23–25). …”

“…As an example, FoxO proteins are considered as therapeutic targets for cancer (23, 82–84), diabetes mellitus (30, 85, 86), and pathways involving oxidative stress (82, 87, 88). Interestingly, FoxO transcription factors also play a significant role in inflammation.…”