Elsevier

Neoplasia

Volume 1, Issue 5, November 1999, Pages 431-437
Neoplasia

Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX1

https://doi.org/10.1038/sj.neo.7900059Get rights and content
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Abstract

The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE), which can be activated through hypoxia-inducible factor-1 (HIF-1). We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

Keywords

hypoxia
brain tumor cells
hypoxia-responsive element
BAX
suicide gene

Abbreviations

Epo
erythropoietin
β-gal
β-galactosidase
HIF-1
hypoxia-inducible factor-1
HRE
hypoxia-responsive element
TUNEL
terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

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1

This work was supported by NIH grant CA-13525. H. R. was supported by NIH grant CA09215. C.-S. L. was supported by the California Breast Cancer Research Program.