Novel liver x receptor ligand gac0001e5 disrupts glutamine metabolism and induces oxidative stress in pancreatic cancer cells

Shivangi Srivastava, Scott Widmann, Charles Ho, Donovan Nguyen, Alexis Nguyen, Asitha Premaratne, Jan Åke Gustafsson, Chin Yo Lin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.

Original languageEnglish (US)
Article number9622
Pages (from-to)1-15
Number of pages15
JournalInternational journal of molecular sciences
Volume21
Issue number24
DOIs
StatePublished - Dec 2 2020

Keywords

  • Glutamine metabolism
  • Ligand
  • Liver X receptor
  • Oxidative stress
  • Pancreatic cancer

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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