Flavopiridol induces cellular FLICE-inhibitory protein degradation by the proteasome and promotes TRAIL-induced early signaling and apoptosis in breast tumor cells.
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.
Palacios
Carmen
C
Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide, Sevilla, Spain.
Yerbes
Rosario
R
López-Rivas
Abelardo
A
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000502:physiology*
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D005419:Flavonoids; D010880:Piperidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C077990:alvocidib; D046988:Proteasome Endopeptidase Complex