To evaluate the role of increased FPPS

To evaluate the role of increased FPPS expression in paclitaxel-treated cells, we investigated the effects of FPPS on Angiotensin I (human, mouse, rat) progression. DNA content analysis showed that the number of cells accumulating in the G/M phase increased in a dose-dependent manner in paclitaxel-treated cells (A and B), however, this increase was noticeably arrested by the overexpression of FPPS. This result suggests that FPPS blocks paclitaxel-induced apoptosis through the regulation of the G2/M phase cell cycle arrest. The present study demonstrates that the overexpression of FPPS attenuates paclitaxel-induced apoptotic cell death through the regulation of the apoptosis-related proteins Bax, Bcl-X, and cytochrome c. The effects of FPPS were mediated by FPP, a catalytic product of FPPS in the mevalonate metabolic pathway . The effect of FPPS on paclitaxel-induced apoptotic cell death was almost completely abolished by the addition of pamidronate, a specific FPPS inhibitor, and the analysis of MAP kinases demonstrated that JNK is involved in the reduction of paclitaxel-induced apoptotic cell death by FPPS. In this study, we found that FPPS renders the human glioblastoma U87MG cells more resistant to apoptotic cell death induced by paclitaxel. FPPS is a key enzyme in isoprenoid biosynthesis, which supplies sesquiterpene precursors for several classes of essential metabolites including sterols, dolichols, and ubiquinones, as well as substrates for the farnesylation of proteins. Protein prenylation is necessary for the correct subcellular localization and function of small GTPases, a large family of signaling proteins that are fundamentally important to the function, survival and malignant transformation of cells , . A previous report has confirmed that FPPS plays a significant anti-apoptotic role in colorectal cancer , and the addition of specific inhibitors of FPPS, such as pamidronate and zoledronate, have been shown to induce apoptosis in human melanoma and breast cancer cells , . In this context, it is of significance that, in our study, the overexpression of FPPS suppressed apoptotic cell death induced by paclitaxel. It is also consistent with our findings in human glioblastoma U87MG cells, which showed that the addition of FPP, a catalytic product of FPPS, attenuated paclitaxel-induced apoptotic cell death. Another study reported that FPP prevents apoptosis induced by the bisphosphonate inhibition of FPPS in hepatocellular carcinoma , in accordance with the results from our study showing that FPPS may disrupt the cellular responses to anti-cancer drugs. Different MAP kinases have been reported to mediate the signal transduction pathways leading to apoptotic cell death in response to paclitaxel . In cancer cells, activation of the JNK signaling cascade was reported to play a key role in paclitaxel-induced apoptotic cell death . In our study, all three MAP kinases studied were activated by paclitaxel. The activation of JNK and p38, but not of ERK, was strongly suppressed by the overexpression of FPPS in paclitaxel-treated cells. However, the JNK-specific inhibitor, SP600125, alone inhibited paclitaxel-induced apoptotic cell death, suggesting that the JNK and p38 pathways do not participate equally in the FPPS-mediated suppression of paclitaxel-induced apoptosis. The overexpression of FPPS noticeably attenuated the paclitaxel-induced cell cycle arrest at the G2/M phase transition. Paclitaxel causes an arrest of the cell cycle at the mitotic phase, and the susceptibility of cancer cells to paclitaxel is dependent upon the expression levels of p53 . Consistent with this concept, we observed increased p53 expression in U87MG cells treated with paclitaxel, and found that the level of p53 was clearly attenuated in U87MG cells overexpressing FPPS. These results suggest that FPPS may regulate apoptotic cell death through the suppression of paclitaxel-induced p53 expression.
-Prenyltransferases catalyze consecutive condensations of isopentenyl diphosphate (IPP) with allylic primer substrates to yield linear prenyl diphosphates with a definite prenyl chain length , . The products are utilized as precursors of glycosyl carrier lipids, namely, undecaprenyl monophosphate and decaprenyl monophosphate in bacteria , , and dolichyl monophosphate in eukaryotes .