Glutamine deprivation counteracts hypoxia-induced chemoresistance
Open accessAbstract
The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for CCA. Glutamine levels were strongly decreased in CCA samples and the growth of established human CCA cell lines was highly dependent on glutamine. Using gradual reduction of external glutamine, we generated derivatives of CCA cell lines which were able to grow without external glutamine (termed glutamine-depleted (GD)). To analyze the effects of coincident oxygen and glutamine deprivation, GD cells were treated with cisplatin or gemcitabine under normoxia and hypoxia. Strikingly, the well-established phenomenon of hypoxia-induced chemoresistance was completely reversed in GD cells. In order to better understand the underlying mechanisms, we focused on the oncogene c-Myc. The combination of cisplatin and hypoxia led to sustained c-Myc protein expression in wildtype cells. In contrast, c-Myc expression was reduced in response to the combinatorial treatment in GD cells, suggesting a functional importance of c-Myc in the process of hypoxia-induced chemoresistance. In summary, these findings indicate that the mechanisms driving adaption to tumor microenvironmental changes and their relevance for the response to therapy are more complex than expected.
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In several cancers, glutamine metabolism is closely related to hypoxia-induced chemoresistance.
“In several cancers, glutamine metabolism is closely related to hypoxia-induced chemoresistance83.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [83]
Adaptation to glutamine deprivation weakens the hypoxia response that normally induces glycolytic enzymes.
“Indeed, the process of adaptation to glutamine deprivation weakens the response to hypoxia, which normally strongly induces the expression of glycolytic enzymes83.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [83]
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- Authors
- Wappler, J., Arts, M., Röth, A., Heeren, R. M. A., Peter Neumann, U., Olde Damink, S. W., Soons, Z., & Cramer, T.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Maastricht University Medical Centre (NL)
- Maastricht University (NL)
- Corresponding author
- Cramer, Thorsten
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 22
- Issue
- 1
- Pages
- 22-32
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC6883317
- OpenAlex
- W2989603336
- Cited by
- 34
- References
- 51
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 4
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (CR 133/2-4)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamine deprivation, cholangiocarcinoma, hypoxia, chemoresistance, tumor microenvironment, c-Myc, cisplatin, gemcitabine, nutrient deprivation
- MeSH terms
- Aged, Aged, 80 and over, Hypoxia, Antineoplastic Agents, Energy Metabolism, Female, Glutamine, Humans, Male, Middle Aged, Oxygen Consumption, Proto-Oncogene Proteins c-myc, Drug Resistance, Neoplasm, Cell Line, Tumor, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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