TY - JOUR
T1 - Inhibition of signal transducer and activator of transcription 3 activity results in down-regulation of Survivin following irradiation
AU - Kim, Kwang Woon
AU - Mutter, Robert W.
AU - Cao, Carolyn
AU - Albert, Jeffrey M.
AU - Shinohara, Eric T.
AU - Sekhar, Konjeti R.
AU - Lu, Bo
PY - 2006/11
Y1 - 2006/11
N2 - Signal transducer and activator of transcription 3 (Stat3) sand Survivin are constitutively up-regulated in various human tumor cells. We previously found Survivin to be significantly reduced in response to radiation in human umbilical vein endothelial cells (HUVEC) but not in tumor cell lines. In this study, we examined the effect of Stat3 on Survivin expression in irradiated HUVECs and breast cancer cells. We also studied how inhibition of Stat3 and Survivin activity affects cell survival and angiogenesis following irradiation. We determined that Survivin was significantly increased by overexpression of an active Stat3 (Stat3-C). Following irradiation, the level of phospho-Stat3 Tyr705, but not phospho-Stat3 Ser727, was reduced in HUVECs, whereas it remained unchanged in irradiated breast cancer cells. Correspondingly, Stat3 DNA-binding activity following irradiation was specifically down-regulated in HUVECs but not in breast cancer cells. Mutation of Tyr705 abolished radiation-induced down-regulation of Survivin. Clonogenic and endothelial cell morphogenesis assays suggested that DN-Stat3 and DN-Survivin together resulted in the greatest radiosensitization of MDA-MB-231, decreasing angiogenesis and cell survival. In summary, Stat3 modulates Survivin, and both are potential therapeutic targets for radiation sensitization in breast cancer.
AB - Signal transducer and activator of transcription 3 (Stat3) sand Survivin are constitutively up-regulated in various human tumor cells. We previously found Survivin to be significantly reduced in response to radiation in human umbilical vein endothelial cells (HUVEC) but not in tumor cell lines. In this study, we examined the effect of Stat3 on Survivin expression in irradiated HUVECs and breast cancer cells. We also studied how inhibition of Stat3 and Survivin activity affects cell survival and angiogenesis following irradiation. We determined that Survivin was significantly increased by overexpression of an active Stat3 (Stat3-C). Following irradiation, the level of phospho-Stat3 Tyr705, but not phospho-Stat3 Ser727, was reduced in HUVECs, whereas it remained unchanged in irradiated breast cancer cells. Correspondingly, Stat3 DNA-binding activity following irradiation was specifically down-regulated in HUVECs but not in breast cancer cells. Mutation of Tyr705 abolished radiation-induced down-regulation of Survivin. Clonogenic and endothelial cell morphogenesis assays suggested that DN-Stat3 and DN-Survivin together resulted in the greatest radiosensitization of MDA-MB-231, decreasing angiogenesis and cell survival. In summary, Stat3 modulates Survivin, and both are potential therapeutic targets for radiation sensitization in breast cancer.
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U2 - 10.1158/1535-7163.MCT-06-0261
DO - 10.1158/1535-7163.MCT-06-0261
M3 - Article
C2 - 17121912
AN - SCOPUS:33845228341
SN - 1535-7163
VL - 5
SP - 2659
EP - 2665
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 11
ER -