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

Martha Foltyn1,2,3, Anna-Luisa Luger1,2,3,4, Nadja I Lorenz1,2,3,4

  • 1Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.

British Journal of Cancer
|February 13, 2019
PubMed
Abstract

Insights

DNA damage-inducible transcript 4 (DDIT4) regulates glioblastoma cell survival and therapy resistance. DDIT4 inhibition sensitizes cells to hypoxia, radiotherapy, and temozolomide, while its overexpression protects them by modulating mTORC1 signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Glioblastoma (GBM) remains a lethal brain cancer despite advances in understanding its genetics.
  • Tumor microenvironment factors like hypoxia and nutrient depletion drive adaptive responses impacting therapy sensitivity.
  • DNA damage-inducible transcript 4 (DDIT4) is a hypoxia-induced protein that inhibits mTORC1 signaling via the TSC1/2 complex.

Purpose of the Study:

  • To investigate the role of DDIT4 in glioblastoma cell adaptation and response to therapy.
  • To develop a glioblastoma cell model to study DDIT4 function under relevant microenvironmental and therapeutic conditions.

Main Methods:

  • Utilized short hairpin RNA (shRNA) for DDIT4 gene suppression.
  • Employed doxycycline-regulated gene induction to control DDIT4 expression.
  • Established a glioblastoma cell model to mimic tumor microenvironment and therapy conditions.

Main Results:

  • Confirmed an inducible DDIT4-mTORC1 signaling axis in human glioblastoma cells, responsive to hypoxia.
  • Observed that temozolomide and radiotherapy treatments could induce DDIT4 and repress mTORC1 activity in certain glioblastoma cell lines.
  • DDIT4 suppression sensitized glioma cells to hypoxia-induced death, whereas DDIT4 overexpression conferred protection.
  • DDIT4 induction protected cells from radiotherapy and temozolomide in clonogenic survival assays, while suppression sensitized them.

Conclusions:

  • DDIT4 acts as a cell-intrinsic regulator of adaptive responses in glioblastoma.
  • DDIT4 contributes to therapy resistance against temozolomide, radiotherapy, and hypoxia by inhibiting mTORC1.
  • Targeting DDIT4 may represent a strategy to overcome glioblastoma therapy resistance.

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