Bortezomib induces apoptosis and growth suppression in human medulloblastoma cells, associated with inhibition of AKT and NFκB signaling, and synergizes with an ERK inhibitor

Fan Yang, Veronica Jove, Shirley Chang, Michael Hedvat, Lucy Liu, Ralf Buettner, Yan Tian, Anna Scuto, Wei Wen, M. L.Richard Yip, Timothy E. Van Meter, Yun Yen, Richard Jove

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Medulloblastoma is the most common brain tumor in children. Here, we report that bortezomib, a proteasome inhibitor, induced apoptosis and inhibited cell proliferation in two established cell lines and a primary culture of human medulloblastomas. Bortezomib increased the release of cytochrome c to cytosol and activated caspase-9 and caspase-3, resulting in cleavage of PARP . Caspase inhibitor (Z-VAD-FMK) could rescue medulloblastoma cells from the cytotoxicity of bortezomib. Phosphorylation of AKT and its upstream regulator mTOR were reduced by bortezomib treatment in medulloblastoma cells. Bortezomib increased the expression of Bad and Bak, pro-apoptotic proteins, and p21Cip1 and p27Kip1, negative regulators of cell cycle progression, which are associated with the growth suppression and induction of apoptosis in these tumor cells. Bortezomib also increased the accumulation of phosphorylated IκBα, and decreased nuclear translocation of NFκB. Thus, NFκB signaling and activation of its downstream targets are suppressed. Moreover, ER K inhibitors or downregulating ER K with ER K siRNA synergized with bortezomib on anticancer effects in medulloblastoma cells. Bortezomib also inhibited the growth of human medulloblastoma cells in a mouse xenograft model. These findings suggest that proteasome inhibitors are potentially promising drugs for treatment of pediatric medulloblastomas.

Original languageEnglish
Pages (from-to)349-357
Number of pages9
JournalCancer Biology and Therapy
Volume13
Issue number6
DOIs
Publication statusPublished - Apr 1 2012
Externally publishedYes

Keywords

  • AKT
  • Apoptosis
  • Bortezomib
  • Brain tumor
  • Erk inhibitor
  • Medulloblastoma
  • NFκB
  • Proliferation

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Yang, F., Jove, V., Chang, S., Hedvat, M., Liu, L., Buettner, R., Tian, Y., Scuto, A., Wen, W., Yip, M. L. R., Van Meter, T. E., Yen, Y., & Jove, R. (2012). Bortezomib induces apoptosis and growth suppression in human medulloblastoma cells, associated with inhibition of AKT and NFκB signaling, and synergizes with an ERK inhibitor. Cancer Biology and Therapy, 13(6), 349-357. https://doi.org/10.4161/cbt.13.6.19239