FOXOs, cancer and regulation of apoptosis

Abstract

Forkhead box O (FOXO) transcription factors are involved in multiple signaling pathways and play critical roles in a number of physiological and pathological processes including cancer. The importance of FOXO factors ascribes them under multiple levels of regulation including phosphorylation, acetylation/deacetylation, ubiquitination and protein-protein interactions. As FOXO factors play a pivotal role in cell fate decision, mounting evidence suggests that FOXO factors function as tumor suppressors in a variety of cancers. FOXOs are actively involved in promoting apoptosis in a mitochondria-independent and -dependent manner by inducing the expression of death receptor ligands, including Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, and Bcl-2 family members, such as Bim, bNIP3 and Bcl-X(L), respectively. An understanding of FOXO proteins and their biology will provide new opportunities for developing more effective therapeutic approaches to treat cancer.

Figure 1

Forkhead box O (FOXO) can induce apoptosis through mitochondria-dependent and -independent pathways. Upregulation of Fas ligand (FasL) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) results in cross-linking and activation of death receptors, which thereby activates caspase-8 and subsequent apoptosis. Direct transcriptional activation of the proapoptotic Bcl-2 family members, such as Bim and bNIP3, or indirectly suppressing the expression of the prosurvival Bcl-2 family member Bcl-X_L by regulating expression of the transcriptional repressor Bcl-6, leads to increase mitochondrial permeability and promote apoptosis. These pathways triggered by FOXOs may operate independently or cooperatively a cell- and/or tissue type-specific manner.