Survivin as a therapeutic target for radiation sensitization in lung cancer.
Expression of survivin is elevated in most malignancies, especially in radiation-resistant cell lines. In this study, we investigated how radiation affects survivin expression in primary endothelial cells as well as in malignant cell lines. We found that 3 Gy significantly reduced survivin protein level in human umbilical vein endothelial cells (HUVECs) but not in tumor cell lines. Flow cytometry studies suggest that the down-regulation of survivin is independent of cell cycle. In addition, survivin mRNA level was also down-regulatable by irradiation. However, it was abrogated by actinomycin D-mediated inhibition of gene transcription. Luciferase reporter gene assays suggest that irradiation suppressed the survivin promoter. p53 overexpression reduced survivin expression, but overexpression of a p53 mutant failed to abolish the radiation-induced down-regulation in HUVECs. Alteration of p53 status in Val138 lung cancer cell line also failed to restore the radiation-inducible down-regulation. Overexpression of survivin in 293 cells prevented apoptosis induced by irradiation and increased cell viability after irradiation. The inhibition of survivin using antisense oligonucleotides caused a significant decrease in cell viability of irradiated H460 lung cancer cells. These data suggest that radiation transcriptionally down-regulates survivin in HUVECs. This regulatory mechanism is defective in malignancies and is not mediated by p53. Survivin overexpression may lead to resistance to radiotherapy by inhibiting apoptosis and enhancing cell viability. The inhibition of survivin results in sensitization of H460 lung cancer cells to radiation. These studies suggest that survivin may be a target for cancer therapy.
Lu
Bo
B
Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. bo.lu@vanderbilt.edu
Mu
Yi
Y
Cao
Carolyn
C
Zeng
Fenghua
F
Schneider
Sylke
S
Tan
Jiahui
J
Price
Jim
J
Chen
Jun
J
Freeman
Michael
M
Hallahan
Dennis E
DE
D004249:DNA Damage / Q000502:physiology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects*; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011836:Radiation Tolerance / Q000502:physiology*; D000077022:Survivin; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D000077022:Survivin; D016159:Tumor Suppressor Protein p53