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Activation of caspase-9 with irradiation inhibits invasion and angiogenesis in SNB19 human glioma cells

Oncogene volume 23, pages 2339–2346 (2004)Cite this article

Abstract

Glioblastoma multiforme, the most common brain tumor, typically exhibits markedly increased angiogenesis, which is crucial for tumor growth and invasion. Antiangiogenic strategies based on disruption of the tumor microvasculature have proven effective for the treatment of experimental brain tumors. Here, we have overexpressed human caspase-9 by stable transfection in the SNB19 glioblastoma cell line, which normally expresses low levels of caspase-9. Our studies revealed that overexpression of caspase-9 coupled with radiation has a synergistic effect on the inhibition of glioma invasion as demonstrated by Matrigel assay (>65%). Furthermore, sense caspase stable clones cocultured with fetal rat brain aggregates along with radiation showed complete inhibition as compared to the parental and vector controls. During in vitro angiogenesis, SNB19 cells cocultured with human microvascular endothelial cells (HMEC) showed vascular network formation after 48–72 h. In contrast, these capillary-like structures were inhibited when HMEC cells were cocultured with sense caspase stable SNB19 cells. This effect was further enhanced by radiation (5 Gy). Signaling mechanisms revealed that apoptosis is induced by cleavage of caspase-9 by radiation, loss of mitochondrial membrane potential and activation of caspase-3. These results demonstrate that activation of caspase-9 disrupts glioma cell invasion and angiogenesis in vitro. Hence, overexpression of proapoptotic molecules such as caspase-9 may be an important determinant of the therapeutic effect of radiation in cancer therapy.

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Abbreviations

VEGF:

vascular endothelial growth factor

HUVEC:

human umbilical vascular endothelial cells

GBMs:

glioblastoma multiforme

PBS:

phosphate buffered saline

DiI:

1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanineperchlorate

DiO:

3,3′-dioctadecyloxacarbocyanine perchlorate

ECM:

extracellular matrix

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Acknowledgements

We thank Karen Minter for preparing the manuscript and Sushma Jasti and Diana Meister for manuscript review. This work was supported by National Cancer Institute Grant CA 75557, CA 85216, CA 92393, CA 95058 and NINDS NS 47699 (to JSR).

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Authors and Affiliations

  1. Department of Biomedical and Therapeutic Sciences, Program of Cancer Biology, University of Illinois College of Medicine, Box 1649, Peoria, 61656, IL, USA

    Niranjan Yanamandra, Shakuntala Kondraganti & Jasti S Rao

  2. Laboratory of Immune Cell Biology, National Cancer Institute NIH, Bethesda, MD, USA

    Srinivasa M Srinivasula

  3. Department of Pathology, University of Illinois College of Medicine, Peoria, IL, USA

    Meena Gujrati

  4. Department of Neurosurgery, University of Illinois College of Medicine, Peoria, IL, USA

    William C Olivero, Dzung H Dinh & Jasti S Rao

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  1. Niranjan Yanamandra
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Correspondence to Jasti S Rao.

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Yanamandra, N., Kondraganti, S., Srinivasula, S. et al. Activation of caspase-9 with irradiation inhibits invasion and angiogenesis in SNB19 human glioma cells. Oncogene 23, 2339–2346 (2004). https://doi.org/10.1038/sj.onc.1207406

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