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PLoS One. 2010 Apr 28;5(4):e10376. doi: 10.1371/journal.pone.0010376.

c-FLIP degradation mediates sensitization of pancreatic cancer cells to TRAIL-induced apoptosis by the histone deacetylase inhibitor LBH589.

Author information

1
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, United States of America.

Abstract

Great efforts have been made to develop novel and efficacious therapeutics against pancreatic cancer to improve the treatment outcomes. Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is such a therapeutic cytokine with selective killing effect toward malignant cells. However, some human pancreatic cancers are intrinsically resistant to TRAIL-mediated apoptosis or therapy. In this study, we have shown that the histone deacetylase inhibitor LBH589 can synergize with TRAIL to augment apoptosis even in TRAIL-resistant cells. LBH589 decreased c-FLIP levels in every tested cell line and survivin levels in some of the tested cell lines. Enforced expression of ectopic c-FLIP, but not survivin, abolished the cooperative induction of apoptosis by the combination of LBH589 and TRAIL, indicating that c-FLIP downregulation plays a critical role in LBH589 sensitization of pancreatic cancer cells to TRAIL. Moreover, LBH589 decreased c-FLIP stability and the presence of the proteasome inhibitor MG132 prevented c-FLIP from reduction by LBH589. Correspondingly, we detected increased levels of ubiqutinated c-FLIP in LBH589-treated cells. These data thus indicate that LBH589 promotes ubiqutin/proteasome-mediated degradation of c-FLIP, leading to downregulation of c-FLIP. Collectively, LBH589 induces c-FLIP degradation and accordingly sensitizes pancreatic cancer cells to TRAIL-induced apoptosis, highlighting a novel therapeutic regimen against pancreatic cancer.

PMID:
20442774
PMCID:
PMC2860986
DOI:
10.1371/journal.pone.0010376
[Indexed for MEDLINE]
Free PMC Article
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