Pterostilbene suppressed irradiation-resistant glioma stem cells by modulating GRP78/miR-205 axis
Thanh-Tuan Huynh1, Chien-Min Lin2, Wei-Hwa Lee3
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam.
Abstract:
Glioblastoma multiforme (GBM) is the most aggressive type characterized by relapse and resistance even with the combination of radio- and chemotherapy. The presence of glioma stem cells (GSCs) has been shown to contribute to tumorigenesis, recurrence and treatment resistance. Particularly, CD133-positive glioma cells have been shown to represent the subpopulation that confers glioma radioresistance and suggested to be the source of tumor recurrence after radiation. Thus, a better understanding and the development of agents which target GSCs could potentially lead to a significant improvement in treating GBM patients. Here, we demonstrated that GRP78 (an antistress protein) was highly expressed in GBM cells along with β-catenin and Notch and correlated to the development of GSCs. CD133+ GSCs exhibited enhanced migration/invasion and self-renewal abilities. When GRP78 was silenced, GSC properties were suppressed and the sensitivity towards irradiation increased. In addition, the level of microRNA 205 appeared to be negatively associated with GRP78 expression. Our previous study indicated that pterostilbene (PT) possessed anticancer stem cell properties in hepatocellular carcinoma. Thus, we examined whether PT is also effective against GSCs. We found that PT-treated GSCs exhibited suppressed self-renewal and irradiation-resistant abilities. PT-mediated effects were associated with an increase of miR-205. Finally, we showed that PT treatment suppressed tumorigenesis in GSC xenograft mice. In conclusion, we provided evidence that GRP78/miR-205 axis played an important role in GSC maintenance and irradiation resistance. PT treatment suppressed GSC development via negatively modulating GRP78 signaling. PT may be considered for combined therapeutic agent to enhance irradiation efficacy in GBM patients.
Insights
Pterostilbene (PT) targets glioma stem cells (GSCs) by inhibiting GRP78 signaling and enhancing radiation sensitivity, offering a potential new therapy for glioblastoma multiforme (GBM). This approach may improve treatment outcomes for GBM patients.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Molecular Therapeutics
Background:
- Glioblastoma multiforme (GBM) is a highly aggressive brain tumor known for treatment resistance and recurrence, often attributed to glioma stem cells (GSCs).
- CD133-positive GSCs are implicated in radioresistance and tumor recurrence, highlighting the need for targeted therapies.
- GRP78, an antistress protein, along with β-catenin and Notch, is associated with GSC development and GBM progression.
Purpose of the Study:
- To investigate the role of GRP78 and microRNA-205 (miR-205) in GSC maintenance and radioresistance.
- To evaluate the efficacy of pterostilbene (PT) as a therapeutic agent against GSCs and its potential to enhance radiotherapy.
Main Methods:
- Analysis of GRP78 expression in GBM cells and its correlation with GSC markers.
- Silencing GRP78 to assess its impact on GSC properties and radiosensitivity.
- Treatment of GSCs with PT and evaluation of self-renewal, invasion, and irradiation resistance.
- Assessment of miR-205 levels in response to GRP78 modulation and PT treatment.
- Xenograft mouse models to evaluate PT's effect on GSC tumorigenesis in vivo.
Main Results:
- High GRP78 expression correlated with GSC development, enhanced migration, invasion, and self-renewal.
- GRP78 silencing reduced GSC properties and increased radiosensitivity.
- PT treatment suppressed GSC self-renewal and radioresistance, associated with increased miR-205 levels.
- PT administration inhibited GSC-driven tumorigenesis in vivo.
Conclusions:
- The GRP78/miR-205 axis is crucial for GSC maintenance and radioresistance in GBM.
- Pterostilbene effectively suppresses GSC development by targeting the GRP78 signaling pathway.
- PT holds promise as a therapeutic agent to enhance the efficacy of radiotherapy for GBM patients.
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