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

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 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.

• Authors: Shuzhen Chen, Lei Fu, Shruti M Raja, Ping Yue, Fadlo R Khuri, Shi-Yong Sun
• Journal: Molecular cancer (Mol Cancer) Vol. 9 Pg. 23 (Jan 29 2010) ISSN: 1476-4598 [Electronic] England
• PMID: 20113484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzamides
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• GGTI 298
• GGTI-DU40
• I-kappa B Proteins
• NFKBIA protein, human
• Pyrazoles
• Pyridines
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• NF-KappaB Inhibitor alpha
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• Proto-Oncogene Proteins c-akt
• rhoB GTP-Binding Protein

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Carcinoma, Non-Small-Cell Lung (enzymology, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• I-kappa B Proteins (metabolism)
• Lung Neoplasms (enzymology, pathology)
• NF-KappaB Inhibitor alpha
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Up-Regulation (drug effects)
• rhoB GTP-Binding Protein (metabolism)