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Publication Detail
Mutant IDH Sensitizes Gliomas to Endoplasmic Reticulum Stress and Triggers Apoptosis via miR-183-Mediated Inhibition of Semaphorin 3E
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Zhang Y, Pusch S, Innes J, Sidlauskas K, Ellis M, Lau J, El-Hassan T, Aley N, Launchbury F, Richard-Loendt A, de Boer J, Chen S, Wang L, von Deimling A, Li N, Brandner S
  • Publisher:
    American Association for Cancer Research
  • Publication date:
  • Journal:
    Cancer Research
  • Status:
  • Country:
    United States
  • Print ISSN:
  • PII:
  • Language:
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 micro-RNA 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, and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR183-semaphorin axis.
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