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Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/51161
Título

Itch/AIP4-independent proteasomal degradation of cFLIP mediates sensitization of breast tumor cells to TRAIL by the histone deacetylase inhibitor SAHA

AutorYerbes, Rosario ; López-Rivas, Abelardo
Palabras claveSAHA
TRAIL
Apoptosis
Breast cancer cells
cFLIP
Itch/AIP4
Fecha de publicaciónabr-2012
EditorSpringer
CitaciónInvestigational New Drugs 30(2): 541-547 (2012)
ResumenThe histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) is undergoing clinical trials as an antitumor drug and has received regulatory approval for cancer treatment. Here, we show that pre-treatment of human breast cancer cells with SAHA makes them susceptible to apoptosis induced by TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). The apoptosis of breast tumour cells induced by TRAIL is blocked at the level of apical activation of caspase-8 and SAHA enhances the TRAIL-induced processing of procaspase-8. Consequently, a TRAIL associated pathway of apoptosis operated via mitochondria is activated in cells treated with SAHA. Interestingly, degradation of cellular FLICE-inhibitory proteins (cFLIPL and cFLIPS) by an ubiquitin/proteasome-dependent Itch/AIP4-independent mechanism is observed upon exposure to SAHA. Targeting cFLIPL directly with siRNA oligonucleotides also sensitizes human breast tumour cells to TRAIL-induced apoptosis. Furthermore, cFLIPL over-expression significantly inhibits the apoptosis elicited through the combined effects of SAHA and TRAIL. Together, these results indicate that SAHA sensitizes breast cancer cells to TRAIL-induced apoptosis by facilitating the activation of early events in the apoptotic TRAIL pathway. Therefore, the combination of TRAIL and SAHA may represent a therapeutic tool to combat breast tumours.
Versión del editorhttp://dx.doi.org/10.1007/s10637-010-9597-x
URIhttp://hdl.handle.net/10261/51161
DOI10.1007/s10637-010-9597-x
Identificadoresissn: 0167-6997
e-issn: 1573-0646
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