{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T06:55:22Z","timestamp":1778914522301,"version":"3.51.4"},"reference-count":18,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JNS"],"published-print":{"date-parts":[[2010,8]]},"abstract":"<jats:sec>\n<jats:title>Object<\/jats:title>\n<jats:p>Nuclear receptor corepressor (N-CoR) forms a complex that maintains neural stem cells in an undifferentiated state through transcriptional repression. Recently, it has been shown that N-CoR is overexpressed in glioblastoma multiforme (GBM) tumor stem cells and has a putative role in maintaining these cells in an undifferentiated immortal state. To determine the effects of disruption of N-CoR complex function by serine\/threonine protein phosphatase 2A (PP2A) inhibition on GBM tumor cell differentiation and proliferation, the authors developed and investigated a competitive small molecule inhibitor (LB1) of PP2A in GBM.<\/jats:p><\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>The authors investigated the effects of LB1 on GBM proliferation and molecular differentiation pathways using in vitro and in vivo studies.<\/jats:p><\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>The LB1 inhibited PP2A, leading to increased levels of phosphorylated Akt kinase and decreased NCoR expression, as well as dose-dependent antiproliferative activity in cultured U87 and U251 malignant glioma cells (dose range 1\u201310 \u03bcM). Systemic LB1 treatment (1.5 mg\/kg\/day for 21 days) had significant tumor antiproliferative effects in mice harboring U87 glioma xenografts (73% mean reduction in tumor volume compared with controls; p &lt; 0.001). Moreover, a reduction in PP2A expression and activity after LB1 treatment in vivo correlated with increased Akt phosphorylation, reduced nuclear N-CoR expression and N-CoR cytoplasmic translocation, and increased accumulation of acetylated core histones, which coincided with the appearance of glial fibrillary acidic protein\u2013expressing tumor cells.<\/jats:p><\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>These findings indicate that PP2A inhibition effectively disrupts N-CoR complex function\/expression and leads to cytoplasmic translocation of N-CoR with subsequent tumor cell differentiation and\/or death. Therapeutic paradigms that target N-CoR function in the cancer stem cell component of malignant gliomas may have treatment utility.<\/jats:p><\/jats:sec>","DOI":"10.3171\/2009.11.jns091272","type":"journal-article","created":{"date-parts":[[2009,12,11]],"date-time":"2009-12-11T15:00:06Z","timestamp":1260543606000},"page":"225-233","source":"Crossref","is-referenced-by-count":34,"title":["The effect of a PP2A inhibitor on the nuclear receptor corepressor pathway in glioma"],"prefix":"10.3171","volume":"113","author":[{"given":"Jie","family":"Lu","sequence":"first","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debbie K.","family":"Song","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gautam U.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Ikejiri","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"Mushlin","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deric M.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell R.","family":"Lonser","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"key":"b1-jns091272","series-title":"Proc Natl Acad Sci U S A","first-page":"19011","article-title":"Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent 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