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Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer

Ru Chen1, Lisa A Lai2, Yumi Sullivan2

  • 1Department of Medicine, University of Washington, Seattle, WA, 98195, USA. ruc@medicine.washington.edu.

Scientific Reports
|August 13, 2017
PubMed

Insights

Targeting glutamine metabolism with 6-diazo-5-oxo-L-norleucine enhances gemcitabine efficacy in chemoresistant pancreatic cancer. This approach disrupts pathways, improving treatment outcomes by altering protein glycosylation and signaling.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Drug Resistance

Background:

  • Pancreatic cancer has a poor prognosis, with gemcitabine as a primary treatment.
  • Drug resistance to gemcitabine significantly limits patient outcomes.
  • Glutamine metabolism is increasingly recognized for its role in drug resistance and immune response.

Purpose of the Study:

  • To investigate the anti-tumor effect of a glutamine analog, 6-diazo-5-oxo-L-norleucine (DON).
  • To determine if DON can sensitize gemcitabine-resistant pancreatic cancer cells.
  • To explore the impact of glutamine metabolism disruption on cancer cell pathways.

Main Methods:

  • Utilized a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant therapy.
  • Disrupted glutamine metabolic pathways in chemoresistant pancreatic cancer cells.
  • Analyzed proteome alterations in cancer cells and secreted exosomes.

Main Results:

  • Disruption of glutamine metabolism improved gemcitabine treatment efficacy.
  • This disruption impacted glycan biosynthesis via the Hexosamine Biosynthesis Pathway (HBP) and cellular redox homeostasis.
  • Observed global changes in protein glycosylation, expression, and function, leading to reduced proliferation and enhanced chemosensitivity.

Conclusions:

  • Targeting glutamine metabolism is a viable strategy to overcome gemcitabine resistance in pancreatic cancer.
  • Disrupting glutamine pathways affects key cellular processes including HBP, redox balance, and protein glycosylation.
  • Proteomic changes, including downregulation of EGFR, AKT-mTOR, and MAPK signaling pathways, correlate with improved chemosensitivity.

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