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Mutant IDH sensitizes gliomas to endoplasmic reticulum stress and triggers apoptosis by MicroRNA183-mediated inhibition of Semaphorin 3E

Zhang, Y; Pusch, S; Innes, J; Sidlauskas, K; Ellis, M; Lau, J; El-Hassan, T; ... Brandner, S; + view all (2019) Mutant IDH sensitizes gliomas to endoplasmic reticulum stress and triggers apoptosis by MicroRNA183-mediated inhibition of Semaphorin 3E. Cancer Research 10.1158/0008-5472.CAN-19-0054. (In press). Green open access

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Abstract

Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating Pten and p53 in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less in vitro and mice with Idh-mutant tumors survived significantly longer compared to Idh-wildtype mice. Comparison of microRNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR183 with the 5' untranslated region of Semaphorin3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis, sensitises tumour cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR183-semaphorin axis.

Type: Article
Title: Mutant IDH sensitizes gliomas to endoplasmic reticulum stress and triggers apoptosis by MicroRNA183-mediated inhibition of Semaphorin 3E
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/0008-5472.CAN-19-0054
Publisher version: https://doi.org/10.1158/0008-5472.CAN-19-0054
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Brain tumours; Isocitrate dehydrogenase; Cre lox system; Glioblastoma; Endoplasmic reticulum stress
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10079645
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