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Titre du document / Document title

Inhibition of IκB kinase by a new class of retinoid-related anticancer agents that induce apoptosis

Auteur(s) / Author(s)

BAYON Yolanda ; ORTIZ Maria A. ; LOPEZ-HERNANDEZ Francisco J. ; FENG GAO ; KARIN Michael ; PFAHL Magnus ; PIEDRAFITA F. Javier ;

Résumé / Abstract

The transcription factor NF-κB 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-KB signaling pathway could therefore be used to induce apoptosis in NF-κB-overexpressing tumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited the activation of NF-κB-dependent transcriptional activity in different tumor cell lines. MX781 was able to completely inhibit tumor necrosis factor alpha-mediated activation of IκB kinase (IKK), the upstream regulator of NF-KB. 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-κB 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 IKKβ kinase-dead mutant or the IκBα 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.

Revue / Journal Title

Molecular and cellular biology    ISSN  0270-7306   CODEN MCEBD4 

Source / Source

2003, vol. 23, no3, pp. 1061-1074 [14 page(s) (article)]

Langue / Language


Editeur / Publisher

American Society for Microbiology, Washington, DC, ETATS-UNIS  (1981) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 19721, 35400010986058.0280

Nº notice refdoc (ud4) : 14649822

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