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Wilms’ tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

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.

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Acknowledgments

We were granted invaluable assistance on this project from a number of people, for which we are deeply appreciative. Specifically, we would like to thank Dr. Lynne Elmore for her advice on immunoblotting and immunofluorescence of H2AX and 53BP1. We are also indebted to Frances White and Julie Farnsworth at the VCU Flow Cytometry Core Facility, supported in part by NIH Grant P30 CA16058, for their many hours that they committed to this project. Further, the help of Dr. Scott Henderson was critical to the epifluorescent and confocal microscopy that were both performed at the VCU Department of Neurobiology & Anatomy Microscopy Facility, supported, in part, with funding from NIH-NINDS Center core grant 5P30NS047463. This work was also supported by the F. Norton Hord, Jr. fund of the Medical College of Virginia Foundation.

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  1. 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

    Mike Y. Chen, Aaron J. Clark, Dana C. Chan, Helen L. Fillmore & William C. Broaddus

  2. Department of Anatomy and Neurobiology, Virginia Commonwealth University Hospitals, Richmond, VA, 23298, USA

    Mike Y. Chen, Aaron J. Clark, Dana C. Chan, Archana Chidambaram, Helen L. Fillmore & William C. Broaddus

  3. Department of Human Genetics and Pathology, Virginia Commonwealth University Hospitals, Richmond, VA, 23298, USA

    Joy L. Ware & Shawn E. Holt

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  1. Mike Y. Chen
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Chen, M.Y., Clark, A.J., Chan, D.C. et al. Wilms’ tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression. J Neurooncol 103, 87–102 (2011). https://doi.org/10.1007/s11060-010-0374-7

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