Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells.

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

doi:10.3390/ijms21249622

Shivangi Srivastava, Asitha Premaratne + Show 6 more

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https://doi.org/10.3390/ijms21249622

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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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, with a 5-year survival rate of 9.3% [1]
We further investigated the transcriptomes of three pancreatic cancer cohorts, namely The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD), Pancreatic Cancer-Canada (PACA-CA), and Pancreatic Cancer-Australia (PACA-AU), as well as normal pancreas tissues from The Genotype-Tissue Expression Project (GTEx) collection
We compared the expression of LXRβ and known target genes SREBF1, ABCA1, ABCG1, FASN, and SCD in pancreatic cancer tissue to normal pancreas tissue and found that transcript levels of LXRβ and its target genes are elevated in the tumor tissues (Figure 1B)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, with a 5-year survival rate of 9.3% [1]. LXR activity can be modulated by endogenous ligands such as oxysterols and synthetic ligands that have been developed to target LXRs in metabolic diseases, including atherosclerosis [5]. LXRs have emerged as druggable targets in cancer therapeutics, and LXR ligands have been shown to elicit antiproliferative effects in multiple cancers, including in our previously published work on pancreatic cancer [6,7]. The LXR inverse agonist SR9243 has been shown to inhibit cancer growth by downregulating aerobic glycolysis and fatty acid synthesis and to affect tumor immunity [9,10]. Targeting cancer metabolism is a promising therapeutic strategy, and metabolic reprogramming driven by oncogenes enables PDACs to survive in hypoxic and nutrient-deprived microenvironments [11]. Targeting glutamine metabolism is an attractive strategy in pancreatic cancer

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