Trends in Cell Biology
Volume 14, Issue 2, February 2004, Pages 64-69
Journal home page for Trends in Cell Biology

NF-κB: tumor promoter or suppressor?

https://doi.org/10.1016/j.tcb.2003.12.004Get rights and content

Abstract

A role for the NF-κB family of transcription factors as tumor promoters is firmly established. However, other data suggest that NF-κB can also inhibit tumor growth. Moreover, NF-κB activity is modulated by tumor suppressors, such as p53 and ARF, whereby NF-κB subunits repress, rather than activate, the expression of tumor-promoting genes. This suggests a dual function of NF-κB during tumor progression – in the early stages, NF-κB inhibits tumor growth but, as further mutations lead to a loss of tumor suppressor expression, the oncogenic functions of NF-κB become unleashed, allowing it to actively contribute to tumorigenesis. Here, I discuss this hypothesis, its implications for NF-κB function, and how this might influence the use of NF-κB-based anticancer therapies.

Section snippets

NF-κB is a tumor promoter

The suggestion that the members of NF-κB family might behave as tumorigenic transcription factors was first put forward upon the cloning of the p50–p105 (NF-κB1) subunit 15, 16. Analysis of the NF-κB1 sequence immediately revealed homology to v-rel, a potent transforming oncogene of the avian reticuloendotheliosis virus [17], and its cellular counterpart the protooncogene c-rel. Further support for a role of NF-κB subunits in cancer came with the discovery of the gene encoding p52–p100 (NF-κB2)

Is NF-κB a tumor suppressor?

DNA damage, oncogene activation and cellular stress are well-established activators of the p53 tumor suppressor; however, they also induce DNA-binding and transcriptional activity of NF-κB [2]. Activation of p53 can result in either cell-cycle arrest or induction of apoptosis, whereas as discussed above, the induction of NF-κB is generally associated with resistance to apoptosis and proliferation. This suggested that mechanisms must exist within the cell to integrate the activities of these two

A revised model for the role of NF-κB in cancer

An important implication of the hypothesis that NF-κB can function as a tumor suppressor is that its behavior in normal untransformed cells might be quite different from that in transformed and malignant tumor cells. Oncogenic stimulation of untransformed cells will not only activate DNA-binding and transcriptional activity of NF-κB but will also activate the tumor suppressor programs of the cell (Figure 2) 12, 13, 21. These tumor suppressors, in particular p53 and ARF, can then act to inhibit

Acknowledgements

N.D.P. is the recipient of a Royal Society University Research Fellowship. Many thanks to Sonia Rocha and Kirsteen Campbell for their critical reading of this manuscript and helpful suggestions.

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