The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma

Martha Foltyn, Anna Luisa Luger, Nadja I. Lorenz, Benedikt Sauer, Michel Mittelbronn, Patrick N. Harter, Joachim P. Steinbach, Michael W. Ronellenfitsch*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

Background: Despite significant advances in the understanding of glioblastoma genetics and biology, survival is still poor. Hypoxia and nutrient depletion in the tumour microenvironment induce adaptive signalling and metabolic responses, which can influence sensitivity to therapeutic regimens. DNA damage-inducible transcript 4 (DDIT4) is a protein induced by hypoxia and in response to DNA stress. Mechanistically, DDIT4 inhibits mammalian target of rapamycin complex 1 (mTORC1) signalling by activation of the tuberous sclerosis 1/2 (TSC1/2) complex. Methods: Using short hairpin RNA-mediated gene suppression as well as doxycycline-regulated gene induction, we developed a glioblastoma cell model to study effects of DDIT4 under conditions of the glioblastoma microenvironment and therapy. Results: We found an intact DDIT4-mTORC1 signalling axis in human glioblastoma cells that was inducible by hypoxia. Temozolomide and radiotherapy also induced DDIT4 and repressed mTORC1 activity in some glioblastoma cell lines. DDIT4 gene suppression sensitised glioma cells towards hypoxia-induced cell death, while DDIT4 overexpression protected them. Additionally, in clonogenic survival analyses, DDIT4 induction conferred protection from radiotherapy and temozolomide, while DDIT4 gene suppression sensitised cells. Conclusions: We identified DDIT4 as a cell-intrinsic regulator for adaptive responses and therapy resistance in glioblastoma cells which may interfere with cell death induction by temozolomide, radiotherapy or hypoxia by inhibiting mTORC1 activity.

Original languageEnglish
Pages (from-to)481-487
Number of pages7
JournalBritish Journal of Cancer
Volume120
Issue number5
DOIs
Publication statusPublished - 5 Mar 2019

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