c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL

• Type of Material: Article
• Authors: Lei Fu, Central South University, Changsha; Yi-Dan Lin, Sichuan University, Chengdu; Heath A. Elrod, Emory University; Ping Yue, Emory University; Youtake Oh, Emory University; Bo Li, Emory University; Hui Tao, Emory University; Georgia Chen, Emory University; Dong M Shin, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2010-12-20
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2010 Fu et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecular-cancer.com/content/9/1/315
• Title of Journal or Parent Work: Molecular Cancer
• ISSN: 1476-4598
• Volume: 9
• Issue: 315
• Start Page: 1
• End Page: 13
• Grant/Funding Information: This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award (to S-Y. S.) and NIH/NCI SPORE P50 grant CA128613 (Project 2 to S-Y. S.).; GZC, DMS, FRK, and SYS are Georgia Cancer Coalition Distinguished Cancer Scholars.
• Research Categories: Health Sciences, Oncology; Biology, Microbiology

Abstract

Background Perifosine, an alkylphospholipid tested in phase II clinical trials, modulates the extrinsic apoptotic pathway and cooperates with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to augment apoptosis. The current study focuses on revealing the mechanisms by which perifosine enhances TRAIL-induced apoptosis. Results The combination of perifosine and TRAIL was more active than each single agent alone in inducing apoptosis of head and neck squamous cell carcinoma cells and inhibiting the growth of xenografts. Interestingly, perifosine primarily increased cell surface levels of DR5 although it elevated the expression of both DR4 and DR5. Blockade of DR5, but not DR4 upregulation, via small interfering RNA (siRNA) inhibited perifosine/TRAIL-induced apoptosis. Perifosine increased phosphorylated c-Jun NH2-terminal kinase (JNK) and c-Jun levels, which were paralleled with DR4 and DR5 induction. However, only DR5 upregulaiton induced by perifosine could be abrogated by both the JNK inhibitor SP600125 and JNK siRNA. The antioxidants, N-acetylcysteine and glutathione, but not vitamin C or tiron, inhibited perifosine-induced elevation of p-c-Jun, DR4 and DR5. Moreover, no increased production of reactive oxygen species was detected in perifosine-treated cells although reduced levels of intracellular GSH were measured. Conclusions DR5 induction plays a critical role in mediating perifosine/TRAIL-induced apoptosis. Perifosine induces DR5 expression through a JNK-dependent mechanism independent of reactive oxygen species.