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Research Articles: Therapeutics, Targets, and Development

Inhibition of signal transducer and activator of transcription 3 activity results in down-regulation of Survivin following irradiation

¹ Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee and ² Department of Radiation Oncology, University of Pennsylvania Health System, Philadelphia, Pennsylvania

Requests for reprints: Bo Lu, Department of Radiation Oncology, Vanderbilt University, B-902 The Vanderbilt Clinic, 1301 22nd Avenue South, Nashville, TN 37232-5671. Phone: 615-343-9233; Fax: 615-343-3075. E-mail: bo.lu{at}vanderbilt.edu

Abstract

Signal transducer and activator of transcription 3 (Stat3) and 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. [Mol Cancer Ther 2006;5(11):2659–65]

Grant support: Vanderbilt Discovery Grant, Vanderbilt Physician Scientist Grant, Mesothelioma Applied Research Foundation, and Department of Defense grants PC031161 and DOD BC030542.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/ 8/06; revised 8/20/06; accepted 9/11/06.

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