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Growth inhibition of malignant glioblastoma by DING protein

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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Abstract

Malignant gliomas are a highly aggressive type of brain tumor with extremely poor prognosis. These tumors are highly invasive and are often surgically incurable and resistant to chemotherapeutics and radiotherapy. Thus, novel therapies that target pathways involved in growth and survival of the tumor cells are required for the treatment of this class of brain tumors. Previous studies revealed that epidermal growth factor receptor and extracellular-signal-regulated kinases (ERKs), which are involved in the induction of cell proliferation, are activated in the most aggressive type of glioma, i.e. glioblastoma multiforme (GBM). In fact, GBMs with increased levels of ERK activity exhibit a more aggressive phenotype than the others with moderate ERK activity, pointing to the importance of ERK and its kinase activity in the development and progression of these tumors. In this study, we have evaluated the effect of p38SJ, a novel member of the DING family of proteins, derived from Hypericum perforatum calluses, on the growth of malignant glioma cell lines, T98G and U-87MG by focusing on cell cycle and signaling pathways controlled by phosphorylation of various regulatory proteins including ERK. p38SJ, which exhibits profound phosphatase activity, shows the capacity to affect the phosphorylation status of several important kinases modulating signaling pathways, and cell growth and proliferation. Our results demonstrate that p38SJ reduces glioma cell viability and arrests cell cycle progression at G0/G1. The observed growth inhibitory effect of p38SJ is likely mediated by the downregulation of several cell cycle gatekeeper proteins, including cyclin E, Cdc2, and E2F-1. These results suggest that p38SJ may serve as a potential candidate for development of a therapeutic agent for the direct treatment of malignant gliomas and/or as a potential radiosensitizer.

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Acknowledgments

The authors wish to thank past and present members of the Department of Neuroscience and Center for Neurovirology for sharing reagents and ideas, and for their continued support. We thank Armine Darbinyan, M.D. for contributing to various aspects of this work, and Samantha Garcia for her assistance with the quantitative analysis of the cell viability assay data. We are grateful to Dr. G. Tuszynski and Dr. M. K. White for critical reading of this manuscript. This work was supported by Tumor Research Grant from Synthes North America to the Temple University School of Medicine Neurosurgery Department, funded, in part, under a grant with the Pennsylvania Department of Health to N. Darbinian, and NIH grants to K. Khalili and S. Amini.

Conflicts of interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Room 741 MERB, 3500 North Broad St., Philadelphia, PA, 19140, USA

    Markus J. Bookland, Nune Darbinian, Shohreh Amini & Kamel Khalili

  2. Department of Neurosurgery, Temple University School of Medicine, Philadelphia, PA, 19140, USA

    Markus J. Bookland & Michael Weaver

  3. Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA

    Shohreh Amini

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  1. Markus J. Bookland
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  2. Nune Darbinian
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  5. Kamel Khalili
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Correspondence to Kamel Khalili.

Additional information

Markus J. Bookland and Nune Darbinian contributed equally to this study.

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Bookland, M.J., Darbinian, N., Weaver, M. et al. Growth inhibition of malignant glioblastoma by DING protein. J Neurooncol 107, 247–256 (2012). https://doi.org/10.1007/s11060-011-0743-x

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