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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Chen, S; Fu, L; Raja, SM; Yue, P; Khuri, FR; Sun, S-Y

Published Date

  • January 29, 2010

Published In

Volume / Issue

  • 9 /

Start / End Page

  • 23 -

PubMed ID

  • 20113484

Pubmed Central ID

  • PMC2824632

Electronic International Standard Serial Number (EISSN)

  • 1476-4598

Digital Object Identifier (DOI)

  • 10.1186/1476-4598-9-23


  • eng

Conference Location

  • England