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

• Published in: Cancer biology & therapy Vol. 13; no. 6; pp. 349 - 357
• Main Authors: Yang, Fan, Jove, Veronica, Chang, Shirley, Hedvat, Michael, Liu, Lucy, Buettner, Ralf, Tian, Yan, Scuto, Anna, Wen, Wei, Yip, M L Richard, Van Meter, Timothy, Yen, Yun, Jove, Richard
• Format: Journal Article
• Language: English
• Published: United States Landes Bioscience 01.04.2012
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-Associated Death Protein - metabolism; Binding; Biology; Bioscience; Boronic Acids - pharmacology; Bortezomib; Calcium; Cancer; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell; Cerebellar Neoplasms - drug therapy; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; Cycle; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cytochromes c - metabolism; Drug Synergism; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Humans; Landes; Medulloblastoma - drug therapy; Medulloblastoma - metabolism; Medulloblastoma - pathology; NF-kappa B - metabolism; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Organogenesis; Phenylurea Compounds - pharmacology; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrazines - pharmacology; Research Paper; Tumor Cells, Cultured
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.19239

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 IĸBα, and decreased nuclear translocation of NF-ĸB. Thus, NF-ĸB signaling and activation of its downstream targets are suppressed. Moreover, ERK inhibitors or downregulating ERK with ERK 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.