Abstract
Primary glioblastomas (GBMs) commonly overexpress the oncogene epidermal growth factor receptor (EGFR), which leads to increased Ras activity. FTA, a novel Ras inhibitor, produced both time- and dose-dependent caspase-mediated apoptosis in GBM cell lines. EGFR-mediated increase in 3H-thymidine uptake was inhibited by FTA. FACS analysis was performed to determine the percent of apoptotic cells. The sub-Go population of GBM cells was increased from 4.5 to 13.8% (control) to over 45–53.6% in FTA-treated cells within 24 h. Furthermore, FTA also increased the activities of both caspase-3 and -9, and PARP cleavage. Treatment of GBMs with FTA before or after EGF addition to the cultures blocked phosphorylation of Akt and mitogen-activated protein kinases (MAPK). FTA also significantly reduced the amount of EGF-induced Ras-GTP as reflected by a decrease in the level of Ras bound to Raf-RBD-GST. This study demonstrates that inhibition of Ras methylation may provide a therapeutic target for the treatment of GBMs overexpressing EGFR.
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Abbreviations
- GBM:
-
Glioblastoma
- FTA:
-
Farnesylthiosalicylic acid
- EGFR:
-
Epidermal Growth Factor Receptor
- MAPK:
-
Mitogen-activated protein kinase
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This work was supported by grants from the National institute of Health, CA 98508 and NS35122 (IMH).
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Amos, S., Redpath, G., Polar, G. et al. Farnesylthiosalicylic acid induces caspase activation and apoptosis in glioblastoma cells. Cell Death Differ 13, 642–651 (2006). https://doi.org/10.1038/sj.cdd.4401783
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DOI: https://doi.org/10.1038/sj.cdd.4401783
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