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Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells

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Abstract

Glioblastoma is the most common and highly malignant brain tumor. It is also one among the most therapy-resistant human neoplasias. Patients die within a year of diagnosis despite the use of available treatment strategies such as surgery, radiotherapy, and chemotherapy. Thus, there is a critical need to find a novel therapeutic strategy for treating this disease. Here, we have investigated the molecular mechanisms for induction of apoptosis as well as for activation of immune components in human malignant glioblastoma T98G and U87MG cells following treatment with all-trans retinoic acid (ATRA) plus interferon-gamma (IFN-γ). Treatment of glioblastoma cells with ATRA alone prevented cell proliferation and induced astrocytic differentiation, while IFN-γ alone induced apoptosis and modulated expression of human leukocyte antigen (HLA) class II molecules such as HLA-DRα, HLA-DR complex, invariant chain (Ii), HLA-DM (an important catalyst of the class II-peptide loading), and gamma interferon-inducible lysosomal thiol-reductase (GILT). Interestingly, both T98G and U87MG cells showed more increase in apoptosis with expression of the HLA class II components for an effective immune response following treatment with ATRA plus IFN-γ than with IFN-γ alone. Apoptotic mode of cell death was confirmed morphologically by Wright staining and biochemically by measuring an increase in caspase-3 activity. While conversion of tumor cells into HLA class II+/Ii- cells by stimulation with the helper CD4+ T cells is thought to be challenging, this study reports for the first time that treatment of glioblastoma cells with ATRA plus IFN-γ can simultaneously enhance apoptosis and expression of the HLA class II immune components with a marked suppression of Ii expression. Taken together, this study suggests that induction of apoptosis and immune components of the HLA class II pathway by ATRA plus IFN-γ may be a promising chemoimmunotherapeutic strategy for treatment of human malignant glioblastoma.

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Acknowledgments

This work was supported in part by the grants from the National Institutes of Health (CA-91460, NS-31622 and NS-57811) and the state of South Carolina (SCIRF-0803), Leukemia and Lymphoma Society, American Cancer Society, Department of Defense, and American Lung Association. We also thank Dr. J. Blum for some of the antibodies and reagents.

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Authors and Affiliations

  1. Department of Neurosciences, Medical University of South Carolina (MUSC), 96 Jonathan Lucas Street, Suite 323K, P.O. Box 250606, Charleston, SC, 29425, USA

    Arabinda Das, Naren L. Banik & Swapan K. Ray

  2. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Azizul Haque, Laela M. Hajiaghamohseni, Austin Younger, Naren L. Banik & Swapan K. Ray

  3. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Azizul Haque, Arabinda Das, Laela M. Hajiaghamohseni, Austin Younger, Naren L. Banik & Swapan K. Ray

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  1. Azizul Haque
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  2. Arabinda Das
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  3. Laela M. Hajiaghamohseni
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Correspondence to Swapan K. Ray.

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Haque, A., Das, A., Hajiaghamohseni, L.M. et al. Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells. Cancer Immunol Immunother 56, 615–625 (2007). https://doi.org/10.1007/s00262-006-0219-6

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  • DOI: https://doi.org/10.1007/s00262-006-0219-6

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