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Alterations in cellular metabolome after pharmacological inhibition of N otch in glioblastoma cells
Author(s) -
Kahlert Ulf D.,
Cheng Menglin,
Koch Katharina,
Marchionni Luigi,
Fan Xing,
Raabe Eric H.,
Maciaczyk Jarek,
Glunde Kristine,
Eberhart Charles G.
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29873
Subject(s) - notch signaling pathway , glutaminase , glutamate receptor , metabolome , cancer research , biology , neurosphere , temozolomide , chemistry , pharmacology , microbiology and biotechnology , metabolite , biochemistry , signal transduction , glioma , cellular differentiation , receptor , gene , adult stem cell
Notch signaling can promote tumorigenesis in the nervous system and plays important roles in stem‐like cancer cells. However, little is known about how Notch inhibition might alter tumor metabolism, particularly in lesions arising in the brain. The gamma‐secretase inhibitor MRK003 was used to treat glioblastoma neurospheres, and they were subdivided into sensitive and insensitive groups in terms of canonical Notch target response. Global metabolomes were then examined using proton magnetic resonance spectroscopy, and changes in intracellular concentration of various metabolites identified which correlate with Notch inhibition. Reductions in glutamate were verified by oxidation‐based colorimetric assays. Interestingly, the alkylating chemotherapeutic agent temozolomide, the mTOR‐inhibitor MLN0128, and the WNT inhibitor LGK974 did not reduce glutamate levels, suggesting that changes to this metabolite might reflect specific downstream effects of Notch blockade in gliomas rather than general sequelae of tumor growth inhibition. Global and targeted expression analyses revealed that multiple genes important in glutamate homeostasis, including glutaminase, are dysregulated after Notch inhibition. Treatment with an allosteric inhibitor of glutaminase, compound 968, could slow glioblastoma growth, and Notch inhibition may act at least in part by regulating glutaminase and glutamate.