Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms.
The observed radioresistance of human glioblastoma multiforme (GBM) poses a major challenge, which, if overcome, may lead to significant advances in the management of this patient population. There is accumulating evidence from correlative studies that Survivin expression is associated with increased malignant potential of human gliomas. The purpose of this study was to investigate whether Survivin plays a direct role in mediating radiation resistance in primary human glioma cell lines, and, if so, investigating the underlying mechanisms. Our panel of GBM cell lines included two that were relatively radiation resistant (GM20 and GM21) and two that were more radiation sensitive (GM22 and GM23), which demonstrated differential levels of Survivin expression between the two groups. Through the use of adenoviral vectors containing either dominant-negative (pAd-S(T34A)) or wild-type Suvrivin (pAd-S(WT)), we were able to inactivate or overexpress Survivin, respectively. Our findings suggest that Survivin plays a critical role in mediating radiation resistance in primary GBM cells, in part through suppression of apoptotic cell death via a caspase-independent manner. We have identified novel mechanisms by which Survivin may enhance tumor cell survival upon radiation exposure such as regulation of double-strand DNA break repair and tumor cell metabolism, which were most evident in the radiation-resistant cell lines. These differences in Survivin function both in radiation-resistant vs radiation-sensitive cell lines and in the presence vs absence of radiation exposure warrant further investigation and highlight potentially important mechanisms of radiation resistance in these tumors.
Chakravarti
Arnab
A
Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston 02114, USA. achakravarti@partners.org
Zhai
Gary G
GG
Zhang
Min
M
Malhotra
Rajeev
R
Latham
Douglas E
DE
Delaney
Meaghan A
MA
Robe
Pierre
P
Nestler
Ulf
U
Song
Qinhui
Q
Loeffler
Jay
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004260:DNA Repair; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins; D011836:Radiation Tolerance / Q000502:physiology*; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D000255:Adenosine Triphosphate; D020169:Caspases