Down-regulation of RIP expression by 17-dimethylaminoethylamino-17-demethoxygeldanamycin promotes TRAIL-induced apoptosis in breast tumor cells.
The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is undergoing clinical trials as an antitumor drug. We show here that treatment of human breast cancer cells with 17DMAG facilitates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Down-regulation of receptor interacting protein (RIP1) is observed upon 17DMAG treatment concomitantly with inhibition of IkappaBalpha phosphorylation. Interestingly, RNAi-mediated knockdown of RIP1 expression is sufficient to sensitize human breast tumor cells to TRAIL-induced apoptosis through a NF-kappaB-independent, mitochondria-operated pathway. Our results indicate that RIP1 is important in maintaining resistance to TRAIL-induced apoptosis in breast tumor cells and highlight the potential therapeutic benefit of the combination of Hsp90 inhibitors and TRAIL against breast tumor cells.
Palacios
Carmen
C
Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Avenida Americo Vespucio s/n, 41092 Sevilla, Spain. carmen.palacios@cabimer.es
López-Pérez
Ana Isabel
AI
López-Rivas
Abelardo
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014162:Transfection
D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D047029:Lactams, Macrocyclic; C000606204:NFKBIA protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000072000:NF-KappaB Inhibitor alpha; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases