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Ran suppresses paclitaxel-induced apoptosis in human glioblastoma cells
Im Sun Woo1, Han-Su Jang, So Young Eun
1Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju 660-751, South Korea.
Abstract:
Yeast-based functional screening of a human glioblastoma cDNA library identified ras-related nuclear protein (Ran) as a novel suppressor of Bcl-2-associated X protein (Bax), a pro-apoptotic member of the Bcl-2 family of proteins. Yeast cells that expressed human Ran were resistant to Bax-induced cell death. In U373MG glioblastoma cells, stable overexpression of Ran significantly attenuated apoptotic cell death induced by the chemotherapeutic agent paclitaxel. FACS analysis demonstrated that Ran is involved in paclitaxel-induced cell cycle arrest. Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel, and inhibited the translocation of Bax, the release of cytochrome c and activation of caspase-3. Paclitaxel-induced phosphorylation of c-JUN N-terminal kinase (JNK), but not p38, extracellular signal-regulated kinase and Akt, was markedly suppressed in U373MG cells that stably expressed Ran. These results suggest that Ran suppresses paclitaxel-induced cell death through the downregulation of JNK-mediated signal pathways.
Insights
Ras-related nuclear protein (Ran) suppresses glioblastoma cell death. Ran inhibits paclitaxel-induced apoptosis by downregulating c-JUN N-terminal kinase (JNK) signaling pathways.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The Bcl-2 family regulates apoptosis, with pro-apoptotic proteins like Bax promoting cell death.
- Glioblastoma is an aggressive brain tumor with limited treatment options.
- Understanding novel regulators of apoptosis is crucial for developing new cancer therapies.
Purpose of the Study:
- To identify novel regulators of apoptosis in glioblastoma.
- To investigate the role of ras-related nuclear protein (Ran) in chemoresistance.
Main Methods:
- Yeast-based functional screening of a human glioblastoma cDNA library.
- Stable overexpression of Ran in U373MG glioblastoma cells.
- Flow cytometry analysis (FACS) to assess cell cycle arrest.
- Western blotting to evaluate protein phosphorylation and activation.
Main Results:
- Ran was identified as a suppressor of Bax-induced cell death.
- Ran overexpression attenuated paclitaxel-induced apoptosis and cell cycle arrest in glioblastoma cells.
- Ran inhibited paclitaxel-induced Bcl-2 phosphorylation, Bax translocation, cytochrome c release, and caspase-3 activation.
- Ran suppressed paclitaxel-induced c-JUN N-terminal kinase (JNK) phosphorylation.
Conclusions:
- Ras-related nuclear protein (Ran) acts as a novel suppressor of apoptosis in glioblastoma.
- Ran inhibits paclitaxel-induced cell death by downregulating JNK-mediated signaling pathways.
- Ran may represent a therapeutic target for enhancing glioblastoma treatment.
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