Universität zu Köln

Dorneburg, Carmen, Goss, Annika V., Fischer, Matthias, Roels, Frederik, Barth, Thomas F. E., Berthold, Frank, Kappler, Roland ORCID: 0000-0002-8581-2803, Oswald, Franz, Siveke, Jens T., Molenaar, Jan J., Debatin, Klaus-Michael ORCID: 0000-0002-8397-1886 and Beltinger, Christian (2016). gamma-secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets. Oncotarget, 7 (39). S. 62799 - 62814. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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Abstract

As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to gamma-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 MYCN-amplified 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dorneburg, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Goss, Annika V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Roels, Frederik UNSPECIFIED UNSPECIFIED UNSPECIFIED Barth, Thomas F. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Kappler, Roland UNSPECIFIED orcid.org/0000-0002-8581-2803 UNSPECIFIED Oswald, Franz UNSPECIFIED UNSPECIFIED UNSPECIFIED Siveke, Jens T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Molenaar, Jan J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Debatin, Klaus-Michael UNSPECIFIED orcid.org/0000-0002-8397-1886 UNSPECIFIED Beltinger, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-262065
DOI:	10.18632/oncotarget.11715
Journal or Publication Title:	Oncotarget
Volume:	7
Number:	39
Page Range:	S. 62799 - 62814
Date:	2016
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACUTE LYMPHOBLASTIC-LEUKEMIA; BREAST-CANCER CELLS; INTRACELLULAR DOMAIN; SIGNALING PATHWAY; GENE-EXPRESSION; E-CADHERIN; APOPTOSIS; BORTEZOMIB; GROWTH; DEATH Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26206