Activating FOXO3a, NF-kappaB and p53 by targeting IKKs: an effective multi-faceted targeting of the tumor-cell phenotype?

Tumor cells frequently recruit the PI3K/Akt pathway in order to evade cell death, terminal differentiation and replicative inhibition. A wealth of targets for the PI3K/Akt pathway involved in these processes has been described. Among others, targets for the Akt-kinase include certain members of the Forkhead Box Class O (FOXO) transcription factors, involved in DNA damage repair, apoptosis, cell cycle progression and arrest. Akt regulates the sub-cellular localization of FOXO3a by phosphorylation thereby preventing the protein to translocate to the nucleus and regulate transcription. Constitutive Akt-activation is frequently correlated with cytoplasmatic FOXO3a in breast tumors and this is associated with decreased patient survival. In a recent paper (Hu MC, et al. Cell 2004; 117:225-237) FOXO3a was found in the cytoplasm in the absence of activated Akt. Instead, IKKbeta was shown to interact with and phosphorylate FOXO3a. The recent findings suggest that the IKKs might serve as a potential drug target in anti-cancer therapy since multiple signal transduction pathways inhibiting proliferation and facilitating cell death could be activated.