Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of Geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis

• Type of Material: Article
• Authors: Shuzhen Chen, Emory University; Lei Fu, Emory University; Shruti M. Raja, Emory University; Ping Yue, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2010
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: ©2010 Chen et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecular-cancer.com/content/9/1/23
• Title of Journal or Parent Work: Molecular Cancer
• ISSN: 1476-4598
• Volume: 9
• Start Page: 23
• End Page: 23
• Grant/Funding Information: This work was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award (to SYS), Department of Defense grant W81XWH-04-1-0142-VITAL (to SYS for Project 4) and NIH/NCI SPORE P50 grant CA128613 (to SYS for Project 2).; FRK and SYS are Georgia Cancer Coalition Distinguished Cancer Scholars.
• Research Categories: Health Sciences, Oncology

Abstract

Background Geranylgeranyltransferase I (GGTase I) has emerged as a cancer therapeutic target. Accordingly, small molecules that inhibit GGTase I have been developed and exhibit encouraging anticancer activity in preclinical studies. However, their underlying anticancer mechanisms remain unclear. Here we have demonstrated a novel mechanism by which GGTase I inhibition modulates apoptosis. Results The GGTase I inhibitor GGTI-298 induced apoptosis and augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. GGTI-298 induced DR4 and DR5 expression and reduced c-FLIP levels. Enforced c-FLIP expression or DR5 knockdown attenuated apoptosis induced by GGTI-298 and TRAIL combination. Surprisingly, DR4 knockdown sensitized cancer cells to GGTI298/TRAIL-induced apoptosis. The combination of GGTI-298 and TRAIL was more effective than each single agent in decreasing the levels of IκBα and p-Akt, implying that GGTI298/TRAIL activates NF-κB and inhibits Akt. Interestingly, knockdown of DR5, but not DR4, prevented GGTI298/TRAIL-induced IκBα and p-Akt reduction, suggesting that DR5 mediates reduction of IκBα and p-Akt induced by GGTI298/TRAIL. In contrast, DR4 knockdown further facilitated GGTI298/TRAIL-induced p-Akt reduction. Conclusions Both DR5 induction and c-FLIP downregulation contribute to GGTI-298-mediated augmentation of TRAIL-induced apoptosis. Moreover, DR4 appears to play an opposite role to DR5 in regulation of GGTI/TRAIL-induced apoptotic signaling.