Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability

dc.contributor.authorSheng, Kevin L.en
dc.contributor.authorPridham, Kevin J.en
dc.contributor.authorSheng, Zhien
dc.contributor.authorLamouille, Samy Y.en
dc.contributor.authorVarghese, Robin T.en
dc.date.accessioned2019-06-03T21:03:10Zen
dc.date.available2019-06-03T21:03:10Zen
dc.date.issued2019-01-08en
dc.description.abstractGlioblastoma, the most common malignant tumor in the brain, lacks effective treatments and is currently incurable. To identify novel drug targets for this deadly cancer, the publicly available results of RNA interference screens from the Project Achilles database were analyzed. Ten candidate genes were identified as survival genes in 15 glioblastoma cell lines. RAN, member RAS oncogene family (RAN) was expressed in glioblastoma at the highest level among all candidates based upon cDNA microarray data. However, Kaplan-Meier survival analysis did not show any correlation between RAN mRNA levels and patient survival. Because RAN is a small GTPase that regulates nuclear transport controlled by karyopherin subunit beta 1 (KPNB1), RAN was further analyzed together with KPNB1. Indeed, GBM patients with high levels of RAN also had more KPNB1 and levels of KPNB1 alone did not relate to patient prognosis. Through a Cox multivariate analysis, GBM patients with high levels of RAN and KPNB1 showed significantly shorter life expectancy when temozolomide and promotermethylation of O6-methylguanine DNA methyltransferase were used as covariates. These results indicate that RAN and KPNB1 together are associated with drug resistance and GBM poor prognosis. Furthermore, the functional blockade of RAN and KPNB1 by importazole remarkably suppressed cell viability and activated apoptosis in GBM cells expressing high levels of RAN, while having a limited effect on astrocytes and GBM cells with undetectable RAN. Together, our results demonstrate that RAN activity is important for GBM survival and the functional blockade of RAN/KPNB1 is an appealing therapeutic approach.en
dc.description.sponsorshipRoanoke Valley Governor Schoolen
dc.format.extent12 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSheng KL, Pridham KJ, Sheng Z, Lamouille S and Varghese RT (2019) Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability. Front. Oncol. 8:662. doi: 10.3389/fonc.2018.00662en
dc.identifier.doihttps://doi.org/10.3389/fonc.2018.00662en
dc.identifier.urihttp://hdl.handle.net/10919/89726en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectRANen
dc.subjectglioblastomaen
dc.subjectimportazoleen
dc.subjectcell survivalen
dc.subjectglioblastoma prognosisen
dc.subjectKPNB1en
dc.subjectglioblastoma treatmenten
dc.titleFunctional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viabilityen
dc.title.serialFrontiers in Oncologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
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