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Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma
1National Brain Research Centre, Department of Molecular and Cellular Neuroscience Division, Manesar, Gurgaon, Haryana 122051, India.
Cell Death & Disease
|May 6, 2016
Summary
This study reveals telomerase regulates cellular metabolism in glioma. Inhibiting human Telomerase reverse transcriptase (hTERT) impacts the pentose phosphate pathway and glycogen, affecting tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Glioma progression involves telomerase activation and altered metabolism.
- The interplay between telomerase and metabolic pathways in glioma remains underexplored.
Purpose of the Study:
- To investigate the connection between telomerase (hTERT) and metabolic dysregulation in glioma.
- To elucidate the role of hTERT in regulating key metabolic pathways and cellular responses.
Main Methods:
- Pharmacological inhibition of hTERT using Costunolide.
- siRNA-mediated knockdown and dominant-negative hTERT (DN-hTERT) expression.
- Analysis of reactive oxygen species (ROS), p53, Nrf2, pentose phosphate pathway (PPP) enzymes (G6PD, TKT), and glycogen metabolism.
- In vivo studies using a xenograft glioma mouse model.
- Analysis of glioblastoma multiforme (GBM) patient tumors with TERT promoter mutations.
Main Results:
- Costunolide induced glioma cell apoptosis via ROS-dependent mechanisms, increasing p53 and abrogating telomerase activity.
- hTERT inhibition decreased Nrf2 levels and key PPP enzymes (G6PD, TKT), leading to increased glycogen accumulation.
- An Nrf2-TERT feedback loop was identified, influencing oxidative defense.
- Costunolide reduced tumor burden in vivo, with decreased TKT activity and increased glycogen/senescence in tumors.
- GBM tumors with TERT mutations showed elevated Nrf2/TKT and reduced glycogen.
Conclusions:
- Telomerase (hTERT) plays a novel role in regulating the pentose phosphate pathway and glycogen accumulation in glioma.
- The Nrf2-TERT axis is crucial for maintaining oxidative defense in glioma cells.
- Targeting hTERT and its associated metabolic pathways presents a potential therapeutic strategy for glioma.
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