Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome

Abstract

Isoprenoid inhibitors are being evaluated as agents for the treatment of cancer. Their antitumor activity is attributed to inhibition of post-translational modification of Ras, which is crucial for its translocation and attachment to the plasma membrane, and ultimate involvement in signal transduction. However, whether blocking of Ras is solely responsible for the observed antitumor activity is unresolved. In this report, we propose an alternate mechanism. Using breast tumor models, we show that agents possessing a lactone moiety, including statins (such as lovastatin) and the isoprenoid inhibitors (such as FTI-277 and GGTI-298), mediate their cell cycle inhibitory activities by blocking the chymotrypsin activity of the proteasome in vitro. This results in the accumulation of cyclin-dependent kinase inhibitors p21 and p27 with subsequent G 1 arrest. Cells devoid of p21 were refractory to the growth-inhibitory activity of lovastatin, FTI-277, and GGTI-298. However, in these p21 null cells, isoprenylation of key substrates of farnesyl transferase (such as Ras) and of geranylgeranyl transferase (such as RAP-1) were inhibited by FTI-277 and GGTI-298, respectively, suggesting that although both these isoprenoid inhibitors reached and inhibited their intended targets, inhibition of the isoprenylation of Ras and RAP-1A are not sufficient to mediate G 1 arrest. We also show that the cell cycle effects can be attributed to the functional lactone moiety of the aforementioned agents. Collectively, our data suggest that FTI and GGTI and other agents containing an active lactone moiety mediate G 1 arrest via inhibition of the proteasome and up-regulation of p21, independent of the inhibition of isoprenylation of Ras or RAP-1. (Cancer Res 2006; 66(2): 1040-51)

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

“…Gene expression in different prostate cancer cell lines is so complex; thus, lovastatin and simvastatin can trigger more apoptosis in one tumor cell line (e.g., LnCaP) but induce both apoptosis and growth arrest in others (PC3 and Du145). Previous studies showed that statins induced different tumor cells to undergo apoptosis by activating caspase-8 or that they induced tumor cell growth arrest at G 1 phase by inducing p21 (28)(29)(30). We observed both phenomena.…”

Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G 0 /G 1 Arrest followed by Necrotic Cell Death in Leishmania donovani

“…The concentration-dependent effect on G 0 /G 1 arrest in promastigotes was largely at the expense of S-phase cells, with low changes in the G 2 /M-phase cell population compared with the untreated pro-mastigotes. The drug-induced cell cycle perturbations, such as an increase in the number of cells in the G 1 phase, have been reported to correlate with a response to chemotherapy (43).…”

The RNA-binding protein Mex3b regulates the spatial organization of the Rap1 pathway

“…We speculated that a mild reduction of Rap1 signaling could rescue the proper localization of N-Cad and Cx43 at the cell surface. To test this idea, Mex3b was silenced in TM4 cells and exposed to the Rap1 inhibitor GGTI-298 (Efuet and Keyomarsi, 2006). Analysis of Rap1-GTP levels by pulldown confirmed the partial inhibition of Rap1 activity after 30 min of exposure to 12.5 μM GGTI (supplementary material Fig.…”