RT info:eu-repo/semantics/article
T1 Inhibition of IκB kinase by a new class of retinoid-related anticancer agents that induce apoptosis
A1 Bayón Prieto, Yolanda
A1 Ortiz, Maria A.
A1 Lopez Hernandez, Francisco J.
A1 Gao, Feng
A1 Karin, Michael
A1 Pfahl, Magnus
A1 Piedrafita, F. Javier
K1 Kinase
K1 Quinasa
K1 Retinoides
K1 Cáncer
K1 24 Ciencias de la Vida
AB The transcription factor NF- B is overexpressed or constitutively activated in many cancer cells, where itinduces expression of antiapoptotic genes correlating with resistance to anticancer therapies. Small moleculesthat inhibit the NF- B signaling pathway could therefore be used to induce apoptosis in NF- B-overexpressingtumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited theactivation of NF- B-dependent transcriptional activity in different tumor cell lines. MX781 was able tocompletely inhibit tumor necrosis factor alpha-mediated activation of I B kinase (IKK), the upstream regulatorof NF- B. Inhibition of IKK activity resulted from direct binding of MX781 to the kinase, as demonstratedby in vitro inhibition studies. Two other molecules, MX3350-1 and CD2325, which are retinoic acidreceptor gamma-selective agonists, were capable of inhibiting IKK in vitro, although they exerted variableinhibition of IKK and NF- 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 nonapoptoticretinoids did not inhibit IKK. Inhibition of IKK by the retinoid-related compounds and other small moleculescorrelated with reduced cell proliferation and increased apoptosis. Reduced cell viability was also observedafter overexpression of an IKK  kinase-dead mutant or the I B  superrepressor. The induction of apoptosisby the retinoid-related molecules that inhibited IKK was dependent on caspase activity but independent of theretinoid receptors. Thus, the presence of an excess of retinoic acid or a retinoid antagonist did not prevent theinhibition of IKK activation by MX781 and CD2325, indicating a retinoid receptor-independent mechanism ofaction.
PB American Society for Microbiology
SN 0270-7306
YR 2003
FD 2003
LK https://uvadoc.uva.es/handle/10324/47498
UL https://uvadoc.uva.es/handle/10324/47498
LA eng
NO Molecular and Cellular Biology, 2003, vol. 23, n. 3, p. 1061-1074
NO Producción Científica
DS UVaDOC
RD 30-abr-2024