c-FLIP Degradation Mediates Sensitization of Pancreatic Cancer Cells to TRAIL-Induced Apoptosis by the Histone Deacetylase Inhibitor LBH589

• Type of Material: Article
• Authors: John Kauh, Emory University; Songqing Fan, Emory University; Mingjing Xia, Emory University; Ping Yue, Emory University; Lily Yang, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2010-04-28
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2010 Kauh et al.
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010376
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 5
• Issue: 4
• Grant/Funding Information: This work was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award (to S-Y. S.) and departmental research fund (to J. K.).
• Research Categories: Health Sciences, Oncology; Biology, Molecular

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.