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Molecular and Cellular Biology, February 2003, p. 1061-1074, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.1061-1074.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inhibition of I{kappa}B Kinase by a New Class of Retinoid-Related Anticancer Agents That Induce Apoptosis

Yolanda Bayon,1 Maria A. Ortiz,1 Francisco J. Lopez-Hernandez,1 Feng Gao,1 Michael Karin,2 Magnus Pfahl,1,3 and F. Javier Piedrafita1*

Sidney Kimmel Cancer Center,1 Maxia Pharmaceuticals,3 Department of Pharmacology, University of California-San Diego School of Medicine, San Diego, California2

Received 1 May 2002/ Returned for modification 11 June 2002/ Accepted 29 October 2002

The transcription factor NF-{kappa}B is overexpressed or constitutively activated in many cancer cells, where it induces expression of antiapoptotic genes correlating with resistance to anticancer therapies. Small molecules that inhibit the NF-{kappa}B signaling pathway could therefore be used to induce apoptosis in NF-{kappa}B-overexpressing tumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited the activation of NF-{kappa}B-dependent transcriptional activity in different tumor cell lines. MX781 was able to completely inhibit tumor necrosis factor alpha-mediated activation of I{kappa}B kinase (IKK), the upstream regulator of NF-{kappa}B. Inhibition of IKK activity resulted from direct binding of MX781 to the kinase, as demonstrated by in vitro inhibition studies. Two other molecules, MX3350-1 and CD2325, which are retinoic acid receptor gamma-selective agonists, were capable of inhibiting IKK in vitro, although they exerted variable inhibition of IKK and NF-{kappa}B activities in intact cells in a cell type-specific manner. However, N-(4-hydroxyphenyl)-retinamide, another apoptosis-inducing retinoid, and retinoic acid as well as other nonapoptotic retinoids did not inhibit IKK. Inhibition of IKK by the retinoid-related compounds and other small molecules correlated with reduced cell proliferation and increased apoptosis. Reduced cell viability was also observed after overexpression of an IKKß kinase-dead mutant or the I{kappa}B{alpha} superrepressor. The induction of apoptosis by the retinoid-related molecules that inhibited IKK was dependent on caspase activity but independent of the retinoid receptors. Thus, the presence of an excess of retinoic acid or a retinoid antagonist did not prevent the inhibition of IKK activation by MX781 and CD2325, indicating a retinoid receptor-independent mechanism of action.

* Corresponding author. Mailing address: 10835 Altman Row, San Diego, CA 92121. Phone: (858) 410-4188. Fax: (858) 450-3251. E-mail: jpiedrafita{at}skcc.org.

Molecular and Cellular Biology, February 2003, p. 1061-1074, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.1061-1074.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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