Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme

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dc.contributor.authorUmans, Robyn A.en
dc.contributor.authorMartin, Joelleen
dc.contributor.authorHarrigan, Megan E.en
dc.contributor.authorPatel, Dipan C.en
dc.contributor.authorChaunsali, Lataen
dc.contributor.authorRoshandel, Aarashen
dc.contributor.authorIyer, Kavyaen
dc.contributor.authorPowell, Michael D.en
dc.contributor.authorOestreich, Kenen
dc.contributor.authorSontheimer, Haralden
dc.date.accessioned2022-09-12T13:51:45Zen
dc.date.available2022-09-12T13:51:45Zen
dc.date.issued2021-12en
dc.description.abstractGlioblastoma multiforme (GBM) is a highly invasive brain tumor that typically has poor patient outcomes. This is due in part to aggressive tumor expansion within the brain parenchyma. This process is aided by assiduous glutamate release via the System xc- (SXC) cystine-glutamate antiporter. SXC is over-expressed in roughly half of GBM tumors where it is responsible for glutamate-mediated neuronal cell death and provides excess glutamate to fuel tumor-associated epilepsy. Available pharmacological inhibitors have some promise, although they lack specificity and have poor bioavailability. Therefore, identifying regulators of SXC may provide a superior avenue to target GBM. In this study, we identify tumor protein 53 (TP53) as a molecular regulator of SXC in GBM. 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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3390/cancers13246169en
dc.identifier.eissn2072-6694en
dc.identifier.issue24en
dc.identifier.other6169en
dc.identifier.pmid34944790en
dc.identifier.urihttp://hdl.handle.net/10919/111798en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectglioblastoma multiformeen
dc.subjectp53en
dc.subjectglutamateen
dc.titleTranscriptional Regulation of Amino Acid Transport in Glioblastoma Multiformeen
dc.title.serialCancersen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Destination Area: Adaptive Brain and Behavior (ABB)