IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a

Abstract

Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IkappaB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKbeta or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKbeta promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.

3-Phosphoinositide-dependent Protein Kinase-1-mediated IκB Kinase β (IKKB) Phosphorylation Activates NF-κB Signaling

“…PDK1 constitutively and moderately activates NF-B through phosphorylation of IKK␤ under nonstimulating conditions, whereas Akt is involved in strong NF-B activation through IKK␣ only when cells are stimulated with TNF-␣. Recently, Hu et al (36) reported a novel cross-talk between the IKK/NF-B and PI3K/PDK1/Akt pathways. They showed that IKK␤ phosphorylated and caused proteolysis of the Forkhead family transcription factor FOXO3a (FKHRL1), which was known to be phosphorylated and excluded from nuclei by Akt (37).…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…In that sense, Hu et al (2004) have shown that IKKb activation in breast cancer cells promotes cell proliferation and suppresses apoptotic potential through phosphorylation and degradation of the proapoptotic factor Foxo3a.…”

FOXO3a nuclear localisation is associated with good prognosis in luminal-like breast cancer

“…However, there is also evidence that an Akt-independent mechanism of FOXO3a regulation exists. In vitro co-transfection of FOXO3a and IKK resulted in strong inhibition of FOXO3a activity independent of Akt [13].…”