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Inhibition of IκB kinase by a new class of retinoid-related anticancer agents that induce apoptosis
BAYON Yolanda ; ORTIZ Maria A. ; LOPEZ-HERNANDEZ Francisco J. ; ...
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 apoptos
American Society for Microbiology
PMID : 12529410 ISSN : 0270-7306 CODEN : MCEBD4
Molecular and cellular biology (Print) A. 2003, vol. 23, n° 3, pp. 1061-1074 [14 pages]
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