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Flavopiridol Induces Cellular FLICE-Inhibitory Protein Degradation by the Proteasome and Promotes TRAIL–Induced Early Signaling and Apoptosis in Breast Tumor Cells

Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide, Sevilla, Spain

Requests for reprints: Abelardo López-Rivas, Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide, Carretera de Utrera km. 1, 41013 Sevilla, Spain. Phone: 34-954-348396; E-mail: alopriv{at}upo.es.

The 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-FLIP_L and c-FLIP_S) 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. (Cancer Res 2006; 66(17): 8858-69)

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