Abstract
Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear receptor known to play an essential role in regulation of cell metabolism, cell proliferation, inflammation, and tumorigenesis in normal and cancer cells. Recently, we found that a newly generated villin-PPARD mouse model, in which PPARD is overexpressed in villin-positive gastric progenitor cells, demonstrated spontaneous development of large, invasive gastric tumors as the mice aged. However, the role of PPARD in regulation of downstream metabolism in normal gastric and tumor cells is elusive. The aim of the present study was to find PPARD-regulated downstream metabolic changes and to determine the potential significance of those changes to gastric tumorigenesis in mice. Hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography-mass spectrometry were employed for metabolic profiling to determine the PPARD-regulated metabolite changes in PPARD mice at different ages during the development of gastric cancer, and the changes were compared to corresponding wild-type mice. Nuclear magnetic resonance spectroscopy-based metabolomic screening results showed higher levels of inosine monophosphate (p = 0.0054), uracil (p = 0.0205), phenylalanine (p = 0.017), glycine (p = 0.014), and isocitrate (p = 0.029) and lower levels of inosine (p = 0.0188) in 55-week-old PPARD mice than in 55-week-old wild-type mice. As the PPARD mice aged from 10 weeks to 35 weeks and 55 weeks, we observed significant changes in levels of the metabolites inosine monophosphate (p = 0.0054), adenosine monophosphate (p = 0.009), UDP-glucose (p = 0.0006), and oxypurinol (p = 0.039). Hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy performed to measure lactate flux in live 10-week-old PPARD mice with no gastric tumors and 35-week-old PPARD mice with gastric tumors did not reveal a significant difference in the ratio of lactate to total pyruvate plus lactate, indicating that this PPARD-induced spontaneous gastric tumor development does not require glycolysis as the main source of fuel for tumorigenesis. Liquid chromatography-mass spectrometry-based measurement of fatty acid levels showed lower linoleic acid, palmitic acid, oleic acid, and steric acid levels in 55-week-old PPARD mice than in 10-week-old PPARD mice, supporting fatty acid oxidation as a bioenergy source for PPARD-expressing gastric tumors.
Highlights
Gastric cancer (GC) is the fifth most common malignancy and third most lethal cancer worldwide, with a 5-year survival rate of 5–10% for GC in advanced stages [1,2,3]
We addressed this knowledge gap using nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography-mass spectrometry (LC-MS), and hyperpolarized [1-13 C] pyruvate magnetic resonance (HP-Magnetic Resonance (MR)) spectroscopy to unravel the downstream metabolic profiling changes governed by Peroxisome proliferator-activated receptor delta (PPARD) in this unique villin-PPARD
We observed that gastric corpus tissues from PPARD mice at age 10 weeks
Summary
Gastric cancer (GC) is the fifth most common malignancy and third most lethal cancer worldwide, with a 5-year survival rate of 5–10% for GC in advanced stages [1,2,3]. GW501516 was found to have a tumor-promoting function in preclinical animal models [6,7,8], and fatty acids in high-fat diets (e.g., arachidonic acid, linoleic acid (LA), and palmitic acid (PA)), serving as natural activating ligands of PPARD [9,10], transformed APC-mutant progenitor cells and promoted colorectal tumorigenesis [6]. All of these data collectively raise concerns about the safety of using PPARD agonists clinically. Disruption of PPARD expression in cancer cells suppresses the development and metastasis of mammary, pancreatic, and colon cancer and melanoma [15,21,22,23]
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