The effect of a PP2A inhibitor on the nuclear receptor corepressor pathway in glioma

Laboratory investigation

Jie Lu Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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 M.D., Ph.D.
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Zhengping Zhuang Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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Debbie K. Song Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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Gautam U. Mehta Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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Barbara Ikejiri Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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Harry Mushlin Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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Deric M. Park Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

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 M.D.
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Russell R. Lonser Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and

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Page Range:
225–233
Volume/Issue:
Volume 113: Issue 2
DOI link:
https://doi.org/10.3171/2009.11.JNS091272
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Object

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.

Methods

The authors investigated the effects of LB1 on GBM proliferation and molecular differentiation pathways using in vitro and in vivo studies.

Results

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 1–10 μM). 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 < 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–expressing tumor cells.

Conclusions

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.

Abbreviations used in this paper:

CNTF = ciliary neurotrophic factor; CSC = cancer stem cell; GBM = glioblastoma multiforme; GFAP = glial fibrillary acidic protein; HDAC = histone deacetylase; N-CoR = nuclear receptor corepressor; PBS = phosphate-buffered saline; PI3K = phosphatidylinositol-3 kinase; PP2A = protein phosphatase 2A; RAR/RXR = retinoic acid receptor/retinoid-X receptor; SCID = severe combined immunodeficient.
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Contributor Notes

Address correspondence to: Russell R. Lonser, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D37, Bethesda, Maryland 20892-1414. email: lonserr@ninds.nih.gov.

Please include this information when citing this paper: published online December 11, 2009; DOI: 10.3171/2009.11.JNS091272.

  • 1

    Andrabi S, , Gjoerup OV, , Kean JA, , Roberts TM, & Schaffhausen B: Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc Natl Acad Sci U S A 104:19011–19016, 2007

    • Search Google Scholar
    • Export Citation
  • 2

    Butler LM, , Agus DB, , Scher HI, , Higgins B, , Rose A, & Cordon-Cardo C, et al.: Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60:5165–5170, 2000

    • Search Google Scholar
    • Export Citation
  • 3

    Fingar DC, , Richardson CJ, , Tee AR, , Cheatham L, , Tsou C, & Blenis J: mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24:200–216, 2004

    • Search Google Scholar
    • Export Citation
  • 4

    Guertin DA, & Sabatini DM: An expanding role for mTOR in cancer. Trends Mol Med 11:353–361, 2005

  • 5

    Hartman HB, , Yu J, , Alenghat T, , Ishizuka T, & Lazar MA: The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3. EMBO Rep 6:445–451, 2005

    • Search Google Scholar
    • Export Citation
  • 6

    Hermanson O, , Jepsen K, & Rosenfeld MG: N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419:934–939, 2002

  • 7

    Janssens V, & Goris J: Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353:417–439, 2001

    • Search Google Scholar
    • Export Citation
  • 8

    Li J, , Wang J, , Wang J, , Nawaz Z, , Liu JM, & Qin J, et al.: Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J 19:4342–4350, 2000

    • Search Google Scholar
    • Export Citation
  • 9

    Manoukian AS, & Woodgett JR: Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res 84:203–229, 2002

    • Search Google Scholar
    • Export Citation
  • 10

    Miller FD, & Gauthier AS: Timing is everything: making neurons versus glia in the developing cortex. Neuron 54:357–369, 2007

  • 11

    Moyal EC, , Laprie A, , Delannes M, , Poublanc M, , Catalaa I, & Dalenc F, et al.: Phase I trial of tipifarnib (R115777) concurrent with radiotherapy in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys 68:1396–1401, 2007

    • Search Google Scholar
    • Export Citation
  • 12

    Ng AP, , Nin DS, , Fong JH, , Venkataraman D, , Chen CS, & Khan M: Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein. Mol Cancer Ther 6:2240–2248, 2007

    • Search Google Scholar
    • Export Citation
  • 13

    Park DM, , Li J, , Okamoto H, , Akeju O, , Kim SH, & Lubensky I, et al.: N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation. Cell Cycle 6:467–470, 2007

    • Search Google Scholar
    • Export Citation
  • 14

    Platta CS, , Greenblatt DY, , Kunnimalaiyaan M, & Chen H: Valproic acid induces Notch1 signaling in small cell lung cancer cells. J Surg Res 148:31–37, 2008

    • Search Google Scholar
    • Export Citation
  • 15

    Singh SK, , Clarke ID, , Terasaki M, , Bonn VE, , Hawkins C, & Squire J, et al.: Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828, 2003

    • Search Google Scholar
    • Export Citation
  • 16

    Stupp R, & Hegi ME: Targeting brain-tumor stem cells. Nat Biotechnol 25:193–194, 2007

  • 17

    Stupp R, , Mason WP, , van den Bent MJ, , Weller M, , Fisher B, & Taphoorn MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996, 2005

    • Search Google Scholar
    • Export Citation
  • 18

    Yamamoto S, , Tanaka K, , Sakimura R, , Okada T, , Nakamura T, & Li Y, et al.: Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res 28:3A 1585–1591, 2008

    • Search Google Scholar
    • Export Citation

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