Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis
- Mol Cancer. 2010 Jan 29;9:23. doi: 10.1186/1476-4598-9-23.
- 1. Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
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 IkappaBalpha and p-Akt, implying that GGTI298/TRAIL activates NF-kappaB and inhibits Akt. Interestingly, knockdown of DR5, but not DR4, prevented GGTI298/TRAIL-induced IkappaBalpha and p-Akt reduction, suggesting that DR5 mediates reduction of IkappaBalpha 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.