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Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells
Wan-Soo Yoon1, Mi-Young Yeom2, Eun-Sun Kang2
1Department of Neurosurgery, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea.
Objective:
Autophagy is one of the key responses of cells to programmed cell death. Memantine, an approved anti-dementia drug, has an antiproliferative effect on cancer cells but the mechanism is poorly understood. The aim of the present study was to test the possibility of induction of autophagic cell death by memantine in glioma cell lines.
Methods:
Glioma cell lines (T-98 G and U-251 MG) were used for this study.
Results:
The antiproliferative effect of memantine was shown on T-98 G cells, which expressed N-methyl-D-aspartate 1 receptor (NMDAR1). Memantine increased the autophagic-related proteins as the conversion ratio of light chain protein 3-II (LC3-II)-/LC3-I and the expression of beclin-1. Memantine also increased formation of autophagic vacuoles observed under a transmission electron microscope. Transfection of small interfering RNA (siRNA) to knock down NMDAR1 in the glioma cells induced resistance to memantine and decreased the LC3-II/LC3-I ratio in T-98 G cells.
Conclusion:
Our study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.
Insights
Memantine, an anti-dementia drug, inhibits glioma cell proliferation by inducing autophagy, a key cell death response. This effect is mediated by the N-methyl-D-aspartate 1 receptor (NMDAR1).
Area of Science:
- Cellular biology
- Neuroscience
- Oncology
Background:
- Autophagy is a critical cellular process involved in programmed cell death.
- Memantine, an anti-dementia medication, exhibits antiproliferative effects on cancer cells, but its underlying mechanisms remain unclear.
- Understanding memantine's mechanism in cancer is crucial for potential therapeutic applications.
Purpose of the Study:
- To investigate whether memantine can induce autophagic cell death in glioma cell lines.
- To elucidate the role of the N-methyl-D-aspartate 1 receptor (NMDAR1) in memantine-induced autophagy.
Main Methods:
- Utilized T-98 G and U-251 MG human glioma cell lines.
- Assessed memantine's antiproliferative effects and its impact on autophagy-related proteins (LC3-II/LC3-I ratio, beclin-1).
- Examined autophagic vacuole formation using transmission electron microscopy and NMDAR1's role via siRNA knockdown.
Main Results:
- Memantine demonstrated antiproliferative effects on T-98 G cells expressing NMDAR1.
- Increased levels of autophagy markers (LC3-II/LC3-I ratio, beclin-1) and autophagic vacuoles were observed with memantine treatment.
- NMDAR1 knockdown via siRNA conferred resistance to memantine and reduced the LC3-II/LC3-I ratio.
Conclusions:
- Memantine effectively inhibits proliferation in NMDAR1-expressing glioma cells.
- The study confirms that memantine induces autophagy in glioma cells.
- NMDAR1 plays a critical role in mediating memantine-induced autophagy and antiproliferative effects.
