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Statin-induced apoptosis via the suppression of ERK1/2 and Akt activation by inhibition of the geranylgeranyl-pyrophosphate biosynthesis in glioblastoma
Abstract
Background: Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition of this key enzyme in the mevalonate pathway leads to suppression of cell proliferation and induction of apoptosis. However, the molecular mechanism of apoptosis induction by statins is not well understood in glioblastoma. In the present study, we attempted to elucidate the mechanism by which statins induce apoptosis in C6 glioma cells. Methods: The cytotoxicity of statins toward the C6 glioma cells were evaluated using a cell viability assay. The enzyme activity of caspase-3 was determined using activity assay kits. The effects of statins on signal transduction molecules were determined by western blot analyses. Results: We found that statins inhibited cell proliferation and induced apoptosis in these cells. We also observed an increase in caspase-3 activity. The apoptosis induced by statins was not inhibited by the addition of farnesyl pyrophosphate, squalene, ubiquinone, and isopentenyladenine, but by geranylgeranyl-pyrophosphate (GGPP). Furthermore, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. Conclusions: These results suggest that statins induce apoptosis when GGPP biosynthesis is inhibited and consequently decreases the level of phosphorylated ERK1/2 and Akt. The results of this study also indicate that statins could be used as anticancer agents in glioblastoma.
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Statins are reported to exert cytotoxic effects against CNS tumour cells.
“Moreover statins are reported to exert cytotoxic effects against CNS tumour cells (Bababeygy et al., 2009;Yanae et al., 2011).”
From The association of statins plus LDL receptor‐targeted liposome‐encapsulated doxorubicin increases in vitro drug delivery across blood–brain barrier cells (2012) · cites this paper as Yanae et al., 2011
A direct anti-tumour activity of statins against glioblastoma cells has been reported previously.
“A direct anti-tumour activity of statins against glioblastoma cells has been reported previously (Bababeygy et al., 2009;Yanae et al., 2011)”
From The association of statins plus LDL receptor‐targeted liposome‐encapsulated doxorubicin increases in vitro drug delivery across blood–brain barrier cells (2012) · cites this paper as Yanae et al., 2011
In rat C6 glioma cells, 5 mmol/L mevastatin and simvastatin induce apoptosis by decreasing intracellular availability of GGPP and activation of ERK1/2 and Akt.
“for instance, in rat C6 glioma cells, 5 mmol•L -1 mevastatin and simvastatin induced apoptosis by decreasing the intracellular availability of GGPP and the activation of ERK1/2 and Akt (Yanae et al., 2011)”
From The association of statins plus LDL receptor‐targeted liposome‐encapsulated doxorubicin increases in vitro drug delivery across blood–brain barrier cells (2012) · cites this paper as Yanae et al., 2011
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Research works printed but not linked: 19
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Pinzón‐Daza, M., Garzón, R., Couraud, P., Romero, I., Weksler, B., Ghigo, D., Bosia, A., & Riganti, C. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02103.x · Cited by 84
Metadata
- Authors
- Yanae, M., Tsubaki, M., Satou, T., Itoh, T., Imano, M., Yamazoe, Y., & Nishida, S.
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2011-08-10
- Volume
- 30
- Issue
- 1
- ISSN
- 1756-9966
- PMC
- PMC3163617
- Cited by
- 110
- References
- 0
- Language
- en
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