ggti-298 and Carcinoma--Non-Small-Cell-Lung

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.. 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.. 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.

Topics: Alkyl and Aryl Transferases; Apoptosis; Benzamides; Carcinoma, Non-Small-Cell Lung; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Screening Assays, Antitumor; Humans; I-kappa B Proteins; Lung Neoplasms; NF-KappaB Inhibitor alpha; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Receptors, TNF-Related Apoptosis-Inducing Ligand; rhoB GTP-Binding Protein; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation