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Int. J. Mol. Sci. 2014, 15(6), 11013-11029; doi:10.3390/ijms150611013
Article

Celecoxib Suppresses the Phosphorylation of STAT3 Protein and Can Enhance the Radiosensitivity of Medulloblastoma-Derived Cancer Stem-Like Cells

1,2,3,4
, 2,3
, 5
, 2,3,4,*  and 2,6,7,*
1 Department of Neurological Surgery, Jan-Ai General Hospital, Taichung 412, Taiwan 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan 3 Department of Neurological Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan 4 Department of Physical Therapy, Hungkuang University, Taichung 433, Taiwan 5 Division of Neurological Surgery, Department of Surgery, Changhua Christian Hospital, Changhua 505, Taiwan 6 Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan 7 Department of Medicine, National Defense Medical Center, Taipei 114, Taiwan
* Authors to whom correspondence should be addressed.
Received: 17 March 2014 / Revised: 27 May 2014 / Accepted: 12 June 2014 / Published: 18 June 2014
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Abstract

Medulloblastoma (MB) is a malignant primary brain tumor with poor prognosis. MB-derived CD133/Nestin double-positive cells (MB-DPs) exhibit cancer stem-like cell (CSC)-like properties that may contribute to chemoradioresistance, tumorigenesis and recurrence. In various tumors, signal transducer and activator of transcription 3 (STAT3) upregulation including MB which can regulate the expression of Nestin. Celecoxib, a selective COX-2 inhibitor, has been shown to potentially reduce STAT3 phosphorylation. The aim of the present study was to investigate the role of celecoxib in enhancing the effects of ionizing radiotherapy (IR) on MB-DP. MB-DPs and MB-derived CD133/Nestin double-negative cells (MB-DNs) were isolated from medulloblastoma cell line Daoy. Then, both of them were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, sphere formation, radiosensitivity, colony formation, apoptotic activity and mouse xenografting experiments in MB-DPs and MB-DNs treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated. We isolated MB-DPs from MB cell line Daoy, which exhibited typical CSC-like characteristics. Microarray analysis and Western blotting both indicated the upregulation of Janus kinase (JAK)-STAT cascade and STAT3 phosphorylation. Incubation with celecoxib dose-dependently suppressed the CSC-like properties and enhanced the IR effect on the induction of apoptosis, as detected by TUNEL assay and staining for Caspase 3 and Annexin V. Finally, celecoxib also enhanced the IR effect to suppress tumorigenesis and synergistically improve the recipient survival in orthotopic MB-derived CD133/Nestin double-positive cells (MB-DP cells) bearing mice.
Keywords: medulloblastoma; STAT3; celecoxib; CD133; Nestin; cancer stem-like cells medulloblastoma; STAT3; celecoxib; CD133; Nestin; cancer stem-like cells
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Yang, M.-Y.; Lee, H.-T.; Chen, C.-M.; Shen, C.-C.; Ma, H.-I. Celecoxib Suppresses the Phosphorylation of STAT3 Protein and Can Enhance the Radiosensitivity of Medulloblastoma-Derived Cancer Stem-Like Cells. Int. J. Mol. Sci. 2014, 15, 11013-11029.

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