Journal of Neuro-Oncology

, Volume 100, Issue 3, pp 449–457 | Cite as

Expression of phosphoprotein enriched in astrocytes 15 kDa (PEA-15) in astrocytic tumors: a novel approach of correlating malignancy grade and prognosis

  • Yosuke Watanabe
  • Fumiyuki Yamasaki
  • Yoshinori Kajiwara
  • Taiichi Saito
  • Takeshi Nishimoto
  • Chandra Bartholomeusz
  • Naoto T. Ueno
  • Kazuhiko Sugiyama
  • Kaoru Kurisu
Clinical Study – Patient Study


Phosphoprotein enriched in astrocytes 15 kDa (PEA-15) is a multifunctional protein that was first identified in brain astrocytes and that has subsequently been shown to be expressed in different tissues. Despite its many important roles, the clinical significance of PEA-15 expression levels in astrocytic tumors has yet to be properly defined. We studied the PEA-15 expression pattern of 65 patients [diagnosed according to World Health Organization (WHO) criteria] with diffuse astrocytoma (WHO grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). PEA-15 expression levels were immunohistochemically measured and categorized as no, low, or high expression. All tumors expressed PEA-15 in our study. Twenty-three (35.4%) and 42 (64.6%) tumors expressed low and high PEA-15 levels, respectively. In grade II astrocytoma (diffuse astrocytoma) and grade III astrocytoma (anaplastic astrocytoma), 100% and 88.9% of patients expressed high PEA-15 levels, respectively, while a smaller number (50%) of patients with grade IV astrocytoma (glioblastoma) expressed high PEA-15 levels. PEA-15 expression level was inversely associated with WHO grade (P = 0.0006). Next, we evaluated prognosis and PEA-15 expression levels in 43 patients with high-grade astrocytomas based on the following parameters: age, gender, WHO grade, surgical resection extent, MIB-1 labeling index (LI), and PEA-15 expression level. Multivariable analyses revealed that high PEA-15 expression level displayed a significant correlation with longer overall survival (OS) in high-grade astrocytomas (P = 0.0024). Patients with total resection survived significantly longer (P = 0.0044) than those with lower resection extent, while patients with MIB-1 labeling index ≤25% indicated significant (P = 0.0434) correlation with OS as well. In conclusion, PEA-15 expression level was inversely associated with WHO grade and may serve as an important prognostic factor for high-grade astrocytomas.


Phosphoprotein enriched in astrocytes 15 kDa Astrocytic tumor Malignancy grade Prognosis Immunohistochemistry 


  1. 1.
    Burnet NG, Lynch AG, Jefferies SJ et al (2007) High grade glioma: imaging combined with pathological grade defines management and predicts prognosis. Radiother Oncol 85:371–378CrossRefPubMedGoogle Scholar
  2. 2.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018CrossRefPubMedGoogle Scholar
  3. 3.
    Daumas-Duport C, Scheithauer B, O’Fallon J et al (1998) Grading of astrocytomas. A simple and reproducible method. Cancer 62:2152–2165CrossRefGoogle Scholar
  4. 4.
    Araujo H, Danziger N, Cordier J et al (1993) Characterization of PEA-15, a major substrate for protein kinase C in astrocytes. J Biol Chem 268:5911–5920PubMedGoogle Scholar
  5. 5.
    Kubes M, Cordier J, Glowinski J et al (1998) Endothelin induces a calcium-dependent phosphorylation of PEA-15 in intact astrocytes: identification of Ser104 and Ser116 phosphorylated, respectively, by protein kinase C and calcium/calmodulin kinase II in vitro. J Neurochem 71:1307–1314CrossRefPubMedGoogle Scholar
  6. 6.
    Trencia A, Perfetti A, Cassese A et al (2003) Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action. Mol Cell Biol 23:4511–4521CrossRefPubMedGoogle Scholar
  7. 7.
    Condorelli G, Vigliotta G, Cafieri A et al (1999) PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 18:4409–4415CrossRefPubMedGoogle Scholar
  8. 8.
    Kitsberg D, Formstecher E, Fauquet M et al (1999) Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis. J Neurosci 19:8244–8251PubMedGoogle Scholar
  9. 9.
    Formstecher E, Ramos JW, Fauquet M et al (2001) PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev Cell 1:239–250CrossRefPubMedGoogle Scholar
  10. 10.
    Krueger J, Chou FL, Glading A et al (2005) Phosphorylation of phosphoprotein enriched in astrocytes (PEA-15) regulates extracellular signal-regulated kinase-dependent transcription and cell proliferation. Mol Biol Cell 16:3552–3561CrossRefPubMedGoogle Scholar
  11. 11.
    Whitehurst AW, Robinson FL, Moore MS et al (2004) The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions. J Biol Chem 279:12840–12847CrossRefPubMedGoogle Scholar
  12. 12.
    Fang JY, Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6:322–327CrossRefPubMedGoogle Scholar
  13. 13.
    Vigliotta G, Miele C, Santopietro S et al (2004) Overexpression of the ped/pea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action. Mol Cell Biol 24:5005–5015CrossRefPubMedGoogle Scholar
  14. 14.
    Zanca C, Garofalo M, Quintavalle C et al (2008) PED is overexpressed and mediates TRAIL resistance in human non-small cell lung cancer. J Cell Mol Med 12:2416–2426CrossRefPubMedGoogle Scholar
  15. 15.
    Garofalo M, Romano G, Quintavalle C et al (2007) Selective inhibition of PED protein expression sensitizes B-cell chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis. Int J Cancer 120:1215–1222CrossRefPubMedGoogle Scholar
  16. 16.
    Todaro M, Zerilli M, Ricci-Vitiani L et al (2006) Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells. Cancer Res 66:1491–1499CrossRefPubMedGoogle Scholar
  17. 17.
    Bartholomeusz C, Rosen D, Wei C et al (2008) PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival. Cancer Res 68:9302–9310CrossRefPubMedGoogle Scholar
  18. 18.
    Glading A, Koziol JA, Krueger J et al (2007) PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2. Cancer Res 67:1536–1544CrossRefPubMedGoogle Scholar
  19. 19.
    Hao C, Beguinot F, Condorelli G et al (2001) Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in human malignant glioma cells. Cancer Res 61:1162–1170PubMedGoogle Scholar
  20. 20.
    Xiao C, Yang BF, Asadi N et al (2002) Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. J Biol Chem 277:25020–25025CrossRefPubMedGoogle Scholar
  21. 21.
    Eckert A, Bock BC, Tagscherer KE et al (2008) The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway. Oncogene 27:1155–1166CrossRefPubMedGoogle Scholar
  22. 22.
    Renault-Mihara F, Beuvon F, Iturrioz X et al (2006) Phosphoprotein enriched in astrocytes-15 kDa expression inhibits astrocyte migration by a protein kinase C delta-dependent mechanism. Mol Biol Cell 17:5141–5152CrossRefPubMedGoogle Scholar
  23. 23.
    Petalidis LP, Oulas A, Backlund M et al (2008) Improved grading and survival prediction of human astrocytic brain tumors by artificial neural network analysis of gene expression microarray data. Mol Cancer Ther 7:1013–1024CrossRefPubMedGoogle Scholar
  24. 24.
    Lopez-Gines C, Gil-Benso R, Benito R et al (2008) The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFR amplification. Neuropathology 28:507–515CrossRefPubMedGoogle Scholar
  25. 25.
    Formisano P, Perruolo G, Libertini S et al (2005) Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. Oncogene 24:7012–7021CrossRefPubMedGoogle Scholar
  26. 26.
    Renganathan H, Vaidyanathan H, Knapinska A et al (2005) Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem J 390:729–735CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Yosuke Watanabe
    • 1
  • Fumiyuki Yamasaki
    • 1
  • Yoshinori Kajiwara
    • 1
  • Taiichi Saito
    • 1
  • Takeshi Nishimoto
    • 1
  • Chandra Bartholomeusz
    • 2
    • 3
  • Naoto T. Ueno
    • 2
    • 3
  • Kazuhiko Sugiyama
    • 1
  • Kaoru Kurisu
    • 1
  1. 1.Department of Neurosurgery, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Department of Breast Medical OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of Stem Cell Transplantation and Cellular TherapyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations