Down-regulation of RIP expression by 17-dimethylaminoethylamino-17-demethoxygeldanamycin promotes TRAIL-induced apoptosis in breast tumor cells

Carmen Palacios; Ana Isabel López-Pérez; Abelardo López-Rivas

doi:10.1016/j.canlet.2009.06.012

Down-regulation of RIP expression by 17-dimethylaminoethylamino-17-demethoxygeldanamycin promotes TRAIL-induced apoptosis in breast tumor cells

Cancer Lett. 2010 Jan 28;287(2):207-15. doi: 10.1016/j.canlet.2009.06.012. Epub 2009 Jul 25.

Authors

Carmen Palacios¹, Ana Isabel López-Pérez, Abelardo López-Rivas

Affiliation

¹ 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

PMID: 19632771
DOI: 10.1016/j.canlet.2009.06.012

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
BH3 Interacting Domain Death Agonist Protein / metabolism
Benzoquinones / pharmacology*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Caspases / metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
Down-Regulation
Enzyme Activation
Female
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
I-kappa B Proteins / metabolism
Lactams, Macrocyclic / pharmacology*
Mitochondria / drug effects
Mitochondria / metabolism
NF-KappaB Inhibitor alpha
Phosphorylation
RNA Interference
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
TNF-Related Apoptosis-Inducing Ligand / metabolism*
Transfection

Substances

Antineoplastic Agents
BH3 Interacting Domain Death Agonist Protein
BID protein, human
Benzoquinones
HSP90 Heat-Shock Proteins
I-kappa B Proteins
Lactams, Macrocyclic
NFKBIA protein, human
TNF-Related Apoptosis-Inducing Ligand
TNFSF10 protein, human
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
NF-KappaB Inhibitor alpha
RIPK1 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases
Caspases