Tumorigenesis: Right place, wrong time

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The I kappa B kinase- beta (IKK beta ) regulates FOXO3A access to the nucleus and, therefore, tumorigenesis.

When members of the FOXO family of transcription factors are located in the nucleus, they activate expression of genes that prevent proliferation and promote apoptosis. Nuclear exclusion of FOXO can therefore contribute to cancer pathogenesis. Hu et al. have discovered a new mechanism that regulates this localization, reporting that the I kappa B kinase- beta (IKK beta ) regulates FOXO3A access to the nucleus and, therefore, tumorigenesis.

When cells are stimulated with growth factors, signalling pathways become activated that lead to phosphorylation of the kinase AKT (AKT-p), which in turn phosphorylates the transcription factors FOXO1, FOXO3A and FOXO4. This causes their localization to the cytoplasm and subsequent cell proliferation. In the absence of growth or survival signalling, however, AKT remains unphosphorylated and inactivate, resulting in the nuclear retention of FOXO factors and the inhibition of cell division — as well as tumour suppression.

Hu et al. investigated the relationships between AKT-p and FOXO3A localization in 131 primary breast tumour specimens. As expected, they observed that FOXO3A was mainly localized to the cytoplasm of tumour cells with a high level of AKT-p and in the nucleus of cells that were AKT-p negative. Surprisingly, they also found a significant number of tumour samples that lacked AKT-p, yet FOXO3A was still confined to the cytoplasm. So is there an alternative mechanism by which cancer cells exclude FOXO3a from the nucleus?

Another cancer-associated kinase that regulates nuclear–cytoplasmic localization of transcription factors is IKK beta , which controls NF- kappa B activity. When Hu et al. examined levels of IKK beta in the tumour samples, they found that the level of nuclear FOXO3A was inversely correlated with the level of this protein. A lack of IKK beta was also correlated with the survival rate of patients with breast cancer. So could IKK beta also contribute to tumorigenesis by keeping FOXO factors out of the nucleus?

Through immunoprecipitation studies, the authors showed that IKK beta physically interacts with and phosphorylates FOXO3A, independently of AKT. Furthermore, IKK beta phosphorylation of FOXO3A leads to its proteolysis through the ubiquitin-dependent proteasome pathway. Hu et al. engineered cells to constitutively express IKK beta and showed that this resulted in loss of FOXO3A activity. In these cells, FOXO3A was no longer present in the nucleus, and therefore did not activate transcription of its target genes. This led to cell-cycle progression and proliferation.

Is constitutive IKK beta activity sufficient to cause tumour formation in vivo? Injection of IKK beta -stably-transfected cells into the mammary fat pad of nude mice caused tumour formation at that location, whereas control cells did not. Re-expression of FOXO3A in these cells, however, suppressed in vivo tumour formation. Therefore, the mechanism underlying IKK beta -mediated tumorigenesis is likely to be through inhibition of FOXO3A.

Hu et al. conclude that as there is an inverse correlation between cytoplasmic FOXO3A in tumour cells and survival in patients with breast cancer, this transcription factor might be a useful prognostic factor, as well as a new tool for therapeutic intervention.

Kristine Novak

References

Hu, M. C.-T. IB kinase promotes tumorigenesis through inhibition of Forkhead FOXO3a. Cell 117, 225–237 (2004) | Article | PubMed |
Kau, T. R., Way, J. C. & Silver, P. A. Nuclear transport and cancer: from mechanism to intervention. Nature Rev. Cancer 4, 106–117 (2004) | Article | PubMed |

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