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MMP-2 siRNA inhibits radiation-enhanced invasiveness in glioma cells
Aruna Venkata Badiga1, Chandramu Chetty, Divya Kesanakurti
1Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America.
Background:
Our previous work and that of others strongly suggests a relationship between the infiltrative phenotype of gliomas and the expression of MMP-2. Radiation therapy, which represents one of the mainstays of glioma treatment, is known to increase cell invasion by inducing MMP-2. Thus, inhibition of MMP-2 provides a potential means for improving the efficacy of radiotherapy for malignant glioma.
Methodology/Principal Findings:
We have tested the ability of a plasmid vector-mediated MMP-2 siRNA (p-MMP-2) to modulate ionizing radiation-induced invasive phenotype in the human glioma cell lines U251 and U87. Cells that were transfected with p-MMP-2 with and without radiation showed a marked reduction of MMP-2 compared to controls and pSV-transfected cells. A significant reduction of proliferation, migration, invasion and angiogenesis of cells transfected with p-MMP-2 and in combination with radiation was observed compared to controls. Western blot analysis revealed that radiation-enhanced levels of VEGF, VEGFR-2, pVEGFR-2, p-FAK, and p-p38 were inhibited with p-MMP-2-transfected cells. TUNEL staining showed that radiation did not induce apoptosis in U87 and U251 cells while a significant increase in TUNEL-positive cells was observed when irradiated cells were simultaneously transfected with p-MMP-2 as compared to controls. Intracranial tumor growth was predominantly inhibited in the animals treated with p-MMP-2 alone or in combination with radiation compared to controls.
Conclusion/Significance:
MMP-2 inhibition, mediated by p-MMP-2 and in combination with radiation, significantly reduced tumor cell migration, invasion, angiogenesis and tumor growth by modulating several important downstream signaling molecules and directing cells towards apoptosis. Taken together, our results demonstrate the efficacy of p-MMP-2 in inhibiting radiation-enhanced tumor invasion and progression and suggest that it may act as a potent adjuvant for radiotherapy in glioma patients.
Insights
Inhibiting matrix metalloproteinase-2 (MMP-2) with a plasmid vector (p-MMP-2) reduced glioma invasion and tumor growth, especially when combined with radiation therapy. This approach shows promise for enhancing glioma treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Glioma invasiveness is linked to matrix metalloproteinase-2 (MMP-2) expression.
- Radiotherapy can enhance glioma cell invasion by increasing MMP-2 levels.
- Targeting MMP-2 offers a strategy to improve radiotherapy outcomes for malignant gliomas.
Purpose of the Study:
- To evaluate the efficacy of plasmid vector-mediated MMP-2 siRNA (p-MMP-2) in modulating radiation-induced invasion in human glioma cells.
- To assess the impact of MMP-2 inhibition on glioma cell proliferation, migration, invasion, and angiogenesis, with and without radiation.
- To investigate the effect of p-MMP-2 on downstream signaling pathways and apoptosis in glioma cells treated with radiation.
Main Methods:
- Transfection of human glioma cell lines (U251, U87) with p-MMP-2.
- Treatment of cells with ionizing radiation, alone or in combination with p-MMP-2.
- Assessment of MMP-2 expression, cell proliferation, migration, and invasion.
- Western blot analysis for VEGF, VEGFR-2, pVEGFR-2, p-FAK, and p-p38.
- TUNEL staining to evaluate apoptosis.
- Evaluation of intracranial tumor growth in animal models.
Main Results:
- p-MMP-2 significantly reduced MMP-2 expression in glioma cells, with or without radiation.
- Combined p-MMP-2 and radiation therapy markedly decreased glioma cell proliferation, migration, invasion, and angiogenesis.
- Radiation-induced increases in VEGF, VEGFR-2, pVEGFR-2, p-FAK, and p-p38 were inhibited by p-MMP-2.
- While radiation alone did not induce apoptosis, co-treatment with p-MMP-2 significantly increased TUNEL-positive cells.
- Intracranial tumor growth was substantially inhibited in animals treated with p-MMP-2, particularly when combined with radiation.
Conclusions:
- MMP-2 inhibition via p-MMP-2, especially combined with radiation, effectively reduces glioma cell migration, invasion, angiogenesis, and tumor growth.
- This therapeutic strategy modulates key downstream signaling molecules and promotes apoptosis.
- p-MMP-2 demonstrates efficacy in counteracting radiation-enhanced tumor invasion and progression.
- p-MMP-2 holds potential as an effective adjuvant therapy for glioma patients undergoing radiotherapy.
