Increased survivin expression confers chemoresistance to tumor-associated endothelial cells.
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.
Virrey
Jenilyn J
JJ
Departments of Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Ave., HMR 315A, Los Angeles, CA 90033, USA.
Guan
Shengxi
S
Li
Wei
W
Schönthal
Axel H
AH
Chen
Thomas C
TC
Hofman
Florence M
FM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply*; D001932:Brain Neoplasms / Q000098:blood supply*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D005910:Glioma / Q000098:blood supply*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin