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: 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:
|
Authors | Martha Foltyn, Anna-Luisa Luger, Nadja I Lorenz, Benedikt Sauer, Michel Mittelbronn, Patrick N Harter, Joachim P Steinbach, Michael W Ronellenfitsch |
Journal | British journal of cancer
(Br J Cancer)
Vol. 120
Issue 5
Pg. 481-487
(03 2019)
ISSN: 1532-1827 [Electronic] England |
PMID | 30745581
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antineoplastic Agents, Alkylating
- DDIT4 protein, human
- Transcription Factors
- Mechanistic Target of Rapamycin Complex 1
- Temozolomide
|
Topics |
- Antineoplastic Agents, Alkylating
(pharmacology)
- Brain Neoplasms
(genetics, metabolism, therapy)
- Cell Line, Tumor
- Drug Resistance, Neoplasm
(genetics)
- Glioblastoma
(genetics, metabolism, therapy)
- HEK293 Cells
- HT29 Cells
- Humans
- Mechanistic Target of Rapamycin Complex 1
(antagonists & inhibitors, metabolism)
- Radiation Tolerance
(genetics)
- Temozolomide
(pharmacology)
- Transcription Factors
(genetics, metabolism)
- Tumor Hypoxia
(genetics)
- Tumor Microenvironment
|