| Autor: |
Umans RA; Center for Glial Biology in Health, Disease and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA., Martin J; Center for Glial Biology in Health, Disease and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA., Harrigan ME; Center for Glial Biology in Health, Disease and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA., Patel DC; Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA., Chaunsali L; Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA., Roshandel A; College of Agriculture and Life Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA., Iyer K; Roanoke College, Salem, VA 24153, USA., Powell MD; Department of Microbiology and Immunity, Emory University School of Medicine, Atlanta, GA 30322, USA., Oestreich K; Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH 43210, USA., Sontheimer H; Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA. |
| Abstrakt: |
Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of SLC7A11 , the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1 Met , results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility. |
