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dc.contributor.authorPalacios, Carmen-
dc.contributor.authorYerbes, Rosario-
dc.contributor.authorLópez-Rivas, Abelardo-
dc.identifierdoi: 10.1158/0008-5472.CAN-06-0808-
dc.identifierissn: 0008-5472-
dc.identifiere-issn: 1538-7445-
dc.identifier.citationCancer Research 66(17): 8858-8869 (2006)-
dc.description.abstractThe cyclin-dependent kinase inhibitor flavopiridol is undergoing clinical trials as an antitumor drug. We show here that pretreatment of different human breast cancer cell lines with flavopiridol facilitates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. In breast tumor cells, apoptosis induction by TRAIL is blocked at the level of apical caspase-8 activation. Flavopiridol treatment enhances TRAIL-induced formation of death-inducing signaling complex and early processing of procaspase-8. Subsequently, a TRAIL-induced, mitochondria-operated pathway of apoptosis is activated in cells treated with flavopiridol. Down-regulation of cellular FLICE-inhibitory proteins (c-FLIP; c-FLIPL and C-FLIPS) is observed on flavopiridol treatment. c-FLIP loss and apoptosis sensitization by flavopiridol are both prevented in cells treated with an inhibitor of the ubiquitin-proteasome system. Furthermore, targeting c-FLIP directly with small interfering RNA oligonucleotides also sensitizes various human breast tumor cell lines to TRAIL-induced apoptosis. Our results indicate that flavopiridol sensitizes breast cancer cells to TRAIL-induced apoptosis by facilitating early events in the apoptotic pathway, and this combination treatment could be regarded as a potential therapeutic tool against breast tumors.-
dc.description.sponsorshipMinisterio de Educación y Ciencia grant SAF-2003-00402 and Association for International Cancer Research (AICR) grant AICR-03-031 (A. López-Rivas), AICR contract (C. Palacios), and Junta de Andalucía and Ministerio de Educación y Ciencia contract (R. Yerbes).-
dc.publisherAmerican Association for Cancer Research-
dc.titleFlavopiridol induces cellular FLICE-inhibitory protein degradation by the proteasome and promotes TRAIL-induced early signaling and apoptosis in breast tumor cells-
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
dc.contributor.funderJunta de Andalucía-
dc.contributor.funderAssociation for International Cancer Research-
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