title: Celecoxib suppresses the phosphorylation of STAT3 protein and can enhance the radiosensitivity of medulloblastoma-derived cancer stem-like cells.
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.
authors.affiliation: Department of Neurological Surgery, Jan-Ai General Hospital, Taichung 412, Taiwan. sdlee@vghtc.gov.tw.
authors.forename: Meng-Yin
authors.initials: MY
authors.lastname: Yang
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan. sdlee@vghtc.gov.tw.
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.affiliation: Division of Neurological Surgery, Department of Surgery, Changhua Christian Hospital, Changhua 505, Taiwan. 96015@cch.org.tw.
authors.forename: Chien-Min
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan. ccshen@vghtc.gov.tw.
authors.forename: Chiung-Chyi
authors.initials: CC
authors.lastname: Shen
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan. uf004693@mail2000.com.tw.
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Ma
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D008527:Medulloblastoma / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D052246:Cyclooxygenase 2 Inhibitors; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011720:Pyrazoles; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D053613:Janus Kinase 1; D000068579:Celecoxib