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

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

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magnolia parka 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 hbl5266ca 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.