Activation of SREBP-1c alters lipogenesis and promotes tumor growth and metastasis in gastric cancer

Biomed Pharmacother. 2020 Aug:128:110274. doi: 10.1016/j.biopha.2020.110274. Epub 2020 May 25.

Abstract

Purpose: Aggressively growing tumors are characterized by significant variations in metabolites, including lipids, and can involve the elevated synthesis ofde novo fatty acids.

Methods: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based metabolomics and lipidomics were performed to compare human gastric cancer tissues and adjacent normal tissues from clinical patients. A series of cellular and molecular biological methods were applied to validate the lipidomics results.

Results: Palmitic acid (PA) was found to be significantly downregulated in gastric cancer tissues, and it was found that a high concentration of PA specifically inhibited cell proliferation and impaired cell invasiveness and migrationin vitro in AGS, SGC-7901, and MGC-803 gastric cancer cell lines. Moreover, sterol regulatory element-binding protein 1 (SREBP-1c) was activated in human gastric cancer tissues, and it promoted the expression of a series of genes associated with the synthesis of fatty acids, such as SCD1 and FASN. SREBP-1c knockdown rescued the migration and invasion defects in AGS and SGC-7901 gastric cancer cells.

Conclusion: Taken together, our findings confirmed the variation in fatty acid synthesis in gastric cancer and identified SREBP-1c as a promising target for gastric cancer treatment.

Keywords: Cancer therapy; Gastric cancer; Lipidomics; Palmitic acid; SREBP-1c.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / secondary
  • Adult
  • Aged
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Proliferation* / drug effects
  • Chromatography, High Pressure Liquid
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lipidomics
  • Lipogenesis*
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Palmitic Acid / pharmacology
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Tandem Mass Spectrometry

Substances

  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Palmitic Acid