TY - JOUR
T1 - Y-secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets
AU - Dorneburg, Carmen
AU - Goß, Annika V.
AU - Fischer, Matthias
AU - Roels, Frederik
AU - Barth, Thomas F.E.
AU - Berthold, Frank
AU - Kappler, Roland
AU - Oswald, Franz
AU - Siveke, Jens T.
AU - Molenaar, Jan J.
AU - Debatin, Klaus Michael
AU - Beltinger, Christian
PY - 2016/9/27
Y1 - 2016/9/27
N2 - As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to y-secretase inhibitor I (GSI-I). NOTCH signaling activity, the cellular effects of GSI-I and its mechanisms of cytotoxicity were evaluated in NB cells in vitro and in vivo. The results show that NOTCH signaling is relevant for human NB cells. Of the GSIs screened in vitro GSI-I was the most effective inhibitor of NB cells. Both MYCNamplified and non-amplified NB cells were susceptible to GSI-I. Among the targets of GSI-I in NB cells were NOTCH and the proteasome. GSI-I caused G2/M arrest that was enhanced by acute activation of MYCN and led to mitotic dysfunction. GSI-I also induced proapoptotic NOXA. Survival of mice bearing an MYCN non-amplified orthotopic patient-derived NB xenograft was significantly prolonged by systemic GSI-I, associated with mitotic catastrophe and reduced angiogenesis, and without evidence of intestinal toxicity. In conclusion, the activity of GSI-I on multiple targets in NB cells and the lack of gastrointestinal toxicity in mice are advantageous and merit further investigations of GSI-I in NB.
AB - As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to y-secretase inhibitor I (GSI-I). NOTCH signaling activity, the cellular effects of GSI-I and its mechanisms of cytotoxicity were evaluated in NB cells in vitro and in vivo. The results show that NOTCH signaling is relevant for human NB cells. Of the GSIs screened in vitro GSI-I was the most effective inhibitor of NB cells. Both MYCNamplified and non-amplified NB cells were susceptible to GSI-I. Among the targets of GSI-I in NB cells were NOTCH and the proteasome. GSI-I caused G2/M arrest that was enhanced by acute activation of MYCN and led to mitotic dysfunction. GSI-I also induced proapoptotic NOXA. Survival of mice bearing an MYCN non-amplified orthotopic patient-derived NB xenograft was significantly prolonged by systemic GSI-I, associated with mitotic catastrophe and reduced angiogenesis, and without evidence of intestinal toxicity. In conclusion, the activity of GSI-I on multiple targets in NB cells and the lack of gastrointestinal toxicity in mice are advantageous and merit further investigations of GSI-I in NB.
KW - Amyloid Precursor Protein Secretases/antagonists & inhibitors
KW - Animals
KW - Apoptosis
KW - Brain Neoplasms/drug therapy
KW - Carbamates/pharmacology
KW - Cell Cycle
KW - Cell Line, Tumor
KW - Dipeptides/pharmacology
KW - Enzyme Inhibitors/pharmacology
KW - Female
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Mice
KW - Mitosis
KW - N-Myc Proto-Oncogene Protein/metabolism
KW - Neoplasm Transplantation
KW - Neovascularization, Pathologic
KW - Neuroblastoma/drug therapy
KW - Oligopeptides/pharmacology
KW - Proteasome Endopeptidase Complex/metabolism
KW - Receptor, Notch1/metabolism
KW - Receptors, Notch/metabolism
KW - Signal Transduction
UR - http://www.scopus.com/inward/record.url?scp=84994030121&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11715
DO - 10.18632/oncotarget.11715
M3 - Article
C2 - 27588497
AN - SCOPUS:84994030121
SN - 1949-2553
VL - 7
SP - 62799
EP - 62813
JO - Oncotarget
JF - Oncotarget
IS - 39
ER -