Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
Open accessAbstract
Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.
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Impairing glutamine metabolism induces sensitivity in gemcitabine-resistant pancreatic cancer cells.
“Impairing glutamine metabolism also induces sensitivity in gemcitabine-resistant pancreatic cancer cells16,84,85.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [84]
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References 58 · Cited by 92
- Authors
- Chen, R., Lai, L. A., Sullivan, Y., Wong, M., Wang, L., Riddell, J., Jung, L., Pillarisetty, V. G., Brentnall, T. A., & Pan, S.
- Affiliations
- University of Washington (US)
- Cell Signaling Technology (United States) (US)
- Corresponding author
- Chen, Ru
- Pan, Sheng
- Venue
- Scientific Reports
- Published
- 2017-08-11
- Volume
- 7
- Issue
- 1
- Pages
- 7950-7950
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5554139
- OpenAlex
- W2745071856
- Cited by
- 92
- References
- 58
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 10 · 2023: 24 · 2022: 13 · 2021: 17 · 2020: 10 · 2019: 8 · 2018: 3
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Michigan
- University of Washington (UWPR95794)
- National Institutes of Health
- National Cancer Institute (R01CA180949, K25CA137222)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- pancreatic cancer, gemcitabine resistance, glutamine metabolism, 6-diazo-5-oxo-L-norleucine, hexosamine biosynthetic pathway, protein glycosylation, redox homeostasis, exosomes, EGFR signaling, Akt/mTOR signaling, MAPK signaling, chemosensitization, proteome changes
- MeSH terms
- Gemcitabine, Cell Survival, Deoxycytidine, Diazooxonorleucine, Drug Synergism, Glutamine, Humans, Oxidation-Reduction, Pancreatic Neoplasms, Drug Resistance, Neoplasm, Proteomics, Cell Line, Tumor, Cell Proliferation, Metabolic Networks and Pathways
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