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PMID: 21127729 Published · ppublish English Journal Article

Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.

Genes & cancer ·Vol. 1 ·No. 8 ·2010-08-00 ·Pages 822-35

Chen J, Kesari S, Rooney C, Strack PR, Chen J, Shen H, Wu L, Griffin JD

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor that is characterized by high proliferative rate and invasiveness. Since dysregulation of Notch signaling is implicated in the pathogenesis of many human cancers, here we investigated the role of Notch signaling in GBM. We found that there is aberrant activation of Notch signaling in GBM cell lines and human GBM-derived neurospheres. Inhibition of Notch signaling via the expression of a dominant negative form of the Notch coactivator, mastermind-like 1 (DN-MAML1), or the treatment of a γ-secretase inhibitor, (GSI) MRK-003, resulted in a significant reduction in GBM cell growth in vitro and in vivo. Knockdown of individual Notch receptors revealed that Notch1 and Notch2 receptors differentially contributed to GBM cell growth, with Notch2 having a predominant role. Furthermore, blockade of Notch signaling inhibited the proliferation of human GBM-derived neurospheres in vitro and in vivo. Our overall data indicate that Notch signaling contributes significantly to optimal GBM growth, strongly supporting that the Notch pathway is a promising therapeutic target for GBM.

Keywords
Notch signaling cell growth glioblastoma tumor neurospheres γ-secretase inhibitor
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Chen Jie
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Kesari Santosh
Rooney Christine
Strack Peter R
Chen Jihua
Shen Huangxuan
Wu Lizi
Griffin James D
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Article Info
Journal
Genes & cancer
Abbr.
Genes Cancer
ISSN
1947-6027
DOI
10.1177/1947601910383564
Published
2010-08-00
Pages
822-35
Language
English
Region
United States
NLM ID
101516546
PMCID
PMC2994256
Grants
NCI NIH HHS · K08 CA124804 · United States
NCI NIH HHS · P01 CA066996 · United States
NCI NIH HHS · P01 CA066996-14 · United States
External Links
PubMed source DOI: 10.1177/1947601910383564 PMC Full Text
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