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Carcinogenesis, Vol. 21, No. 9, 1757-1760, September 2000
© 2000 Oxford University Press

Short Communications

A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin

Sabina C. Cosulich2, Neil H. James1, Maurice R.C. Needham, Peter P. Newham, Ken R. Bundell and Ruth A. Roberts1

AstraZeneca Pharmaceuticals and
1 Zeneca Central Toxicology Laboratory, 3G8 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocyte cultures, PPs suppress spontaneous apoptosis and that induced by a number of pro-apoptotic stimuli such as transforming growth factor-ß1. Tumour necrosis factor {alpha} (TNF-{alpha}) and the transcription factor NF{kappa}B have been implicated in the mode of action of PPs. TNF-{alpha} signalling to NF{kappa}B is thought to be responsible for many of the effects elicited by this cytokine. NF{kappa}B regulates gene expression in immunity, stress responses and the inhibition of apoptosis. Activation of NF{kappa}B requires the successive action of NF{kappa}B-inducing kinase and the phosphorylation of NF{kappa}B inhibitory proteins (I{kappa}B) by an I{kappa}B kinase (IKK) complex. The IKK2 subunit of I{kappa}B kinase is thought to be essential for NF{kappa}B activation and prevention of apoptosis. To determine whether IKK2 plays a role in the suppression of apoptosis by PPs, we expressed a dominant negative form of IKK2 (IKK2dn) in primary rat hepatocyte cultures. Infection with an adenovirus construct expressing IKK2dn caused apoptosis in control primary rat hepatocytes in the absence of exogenous TNF-{alpha}. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-{alpha} or the peroxisome proliferator nafenopin. These results demonstrate a requirement for intracellular signalling pathways mediated by IKK2 in the suppression of apoptosis by the PP class of hepatocarcinogens.


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