CANCER BIOLOGY IKK: Another Path to FOXO Inhibition

Members of the Forkhead family of transcription factors are involved in cellular processes and have been implicated as contributors to tumorigenesis. One known pathway that inhibits the transcriptional regulatory activity of members of the Forkhead subfamily FOXO is the phosphoinositide 3-kinase (PI3K) pathway. Hu et al. now show that there is an inverse correlation between the abundance of IB kinase ß (IKKß) and the localization of FOXO3a to the nucleus in human breast cancer specimens and that this cytosolic sequestration of FOXO3a can occur in the absence of phosphorylated Akt (a downstream component in the PI3K pathway). Cotransfection of FOXO3a and IKKß inhibited expression of a FOXO-responsive reporter gene, including ones containing the p21Kip1 promoter (p21Kip1 contributes to cell cycle arrest in G₁). In the cotransfected cells, FOXO3a was excluded from the nucleus; whereas, in cells only transfected to produce FOXO3a, the protein was found in both the nucleus and cytosol. Indeed endogenous and transfected FOXO3a and IKKß coimmunoprecipitated and the amount of the complex was increased by inhibition of the proteasome and treatment of cells with tumor necrosis factor (TNF-). IKKß phosphorylated and stimulated the ubiquitination of FOXO3a, which resulted in its degradation by the proteasome. Forced expression of FOXO3a in IKKß overexpressing cells inhibited their proliferation and decreased their tumorigenicity in nude mice. Thus, there appears to be complex interplay between the NF-B pathway and the FOXO pathway controlling cell proliferation at the level of IKK, and this convergence may contribute to the uncontrolled growth seen in human cancers.

M. C.-T. Hu, D.-F. Lee, W. Xia, L. S. Golfman, F. Ou-Yang, J.-Y. Yang, Y. Zou, S. Bao, N. Hanada, H. Saso, R. Kobayashi, M.-C. Hung, IB kinase promotes tumorigenesis through inhibition of Forkhead FOXO3a. Cell 117, 225-237 (2004). [Online Journal]

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