Wilms' tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression.
Wilms' tumor 1 (WT1) is a transcription factor with a multitude of downstream targets that have wide-ranging effects in non-glioma cell lines. Though its expression in glioblastomas is now well-documented, the role of WT1 in these tumors remains poorly defined. We hypothesized that WT1 functions as an oncogene to enhance glioblastoma viability and chemoresistance. WT1's role was examined by studying the effect of WT1 silencing and overexpression on DNA damage, apoptosis and cell viability. Results indicated that WT1 silencing adversely affected glioblastoma viability, at times, in synergy with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin. To investigate other mechanisms through which WT1 could affect viability, we measured cell cycle distribution, senescence, and autophagy. WT1 silencing had no effect on these processes. Lastly, we examined WT1 regulation of IGF-1R expression. Counterintuitively, upregulation of IGF-1R was evident after WT1 silencing. In conclusion, WT1 functions as a survival factor in glioblastomas, possibly through inhibition of IGF-1R expression.
Chen
Mike Y
MY
Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Hospitals, Virginia Commonwealth University Health System, P.O. Box 980631, Richmond, VA 23298-0631, USA.
Clark
Aaron J
AJ
Chan
Dana C
DC
Ware
Joy L
JL
Holt
Shawn E
SE
Chidambaram
Archana
A
Fillmore
Helen L
HL
Broaddus
William C
WC
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002330:Carmustine / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000235:genetics*
D034741:RNA, Small Interfering; D025721:WT1 Proteins; D017526:Receptor, IGF Type 1; D002945:Cisplatin; D002330:Carmustine
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