Published online before print July 3, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.071079

Accepted for publication May 13, 2008.

Article

Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

Jenilyn J. Virrey^*, Shengxi Guan, Wei Li, Axel H. Schönthal, Thomas C. Chen^*¶, and Florence M. Hofman^*@

From the Departments of Pathology,* Biochemistry, Dermatology, Molecular Microbiology and Immunology, and Neurosurgery,^¶ University of Southern California, Keck School of Medicine, Los Angeles, California

^@ To whom correspondence should be addressed. E-mail: hofman{at}usc.edu.

	Abstract

Growing evidence suggests that survivin, a member of the inhibitor of apoptosis gene family, is responsible for drug resistance in cancer cells, yet little is known about its role in the endothelial cells of the tumor vasculature. We have previously reported that tumor-associated endothelial cells derived from gliomas (TuBECs) are resistant to anticancer chemotherapy whereas normal brain endothelial cells (BECs) are sensitive. The focus of this study is to investigate the mechanism behind this chemoresistance. Here we show that survivin is constitutively overexpressed in the glioma vasculature but not in the blood vessels of normal brain. To determine whether survivin contributes to TuBEC chemoresistance, we used a lentiviral siRNA system or the drug roscovitine to down-regulate survivin expression. Reduced levels of survivin sensitized TuBECs to the chemotherapeutic agents VP-16, paclitaxel, thapsigargin, and temozolomide. This cell death was mediated through caspases 7 and 4. Conversely, forced expression of survivin in BECs was protective against drug cytotoxicity. These data suggest that overexpression of survivin in endothelial cells serves as a protective mechanism that defends the vasculature from drug cytotoxicity. Our studies demonstrate that targeting survivin may be an effective approach to chemosensitization and anti-vascular therapy for brain tumors.