Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E2 and suppress tumor growth in medulloblastoma

Life Sci. 2022 Apr 15:295:120394. doi: 10.1016/j.lfs.2022.120394. Epub 2022 Feb 11.

Abstract

Aims: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the ω3-long chain polyunsaturated fatty acids (ω3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model.

Main methods: Effects of ω3-LCPUFA treatment of MB cells were assessed using the following: WST-1 assay, cell death probes, clonogenic assay, ELISA and western blot. MB cells were implanted into nude mice and the mice were randomized to DHA, or a combination of DHA and EPA treatment, or to control group. Treatment effects in tumor tissues were evaluated with: LC-MS/MS, RNA-sequencing and immunohistochemistry, and tumors, erythrocytes and brain tissues were analyzed with gas chromatography.

Key findings: ω3-LCPUFA decreased prostaglandin E2 (PGE2) secretion from MB cells, and impaired MB cell viability and colony forming ability and increased apoptosis in a dose-dependent manner. DHA reduced tumor growth in vivo, and both PGE2 and prostacyclin were significantly decreased in tumor tissue from treated mice compared to control animals. All ω3-LCPUFA and dihomo-γ-linolenic acid increased in tumors from treated mice. RNA-sequencing revealed 10 downregulated genes in common among ω3-LCPUFA treated tumors. CRYAB was the most significantly altered gene and the downregulation was confirmed by immunohistochemistry.

Significance: Our findings suggest that addition of DHA and EPA to the standard MB treatment regimen might be a novel approach to target inflammation in the tumor microenvironment.

Keywords: CRYAB; Dihomo-γ-linolenic acid; Docosahexaenoic acid; Docosapentaenoic acid; Eicosapentaenoic acid; Pediatric cancer; Prostacyclin; Thromboxane.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromatography, Liquid / methods
  • Dinoprostone / metabolism
  • Docosahexaenoic Acids / pharmacology
  • Eicosapentaenoic Acid / pharmacology
  • Fatty Acids / metabolism
  • Fatty Acids, Omega-3 / metabolism
  • Fatty Acids, Omega-3 / pharmacology*
  • Female
  • Humans
  • Medulloblastoma / drug therapy*
  • Medulloblastoma / metabolism*
  • Mice
  • Mice, Nude
  • Prostaglandins / metabolism
  • Tandem Mass Spectrometry / methods
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays / methods
  • alpha-Crystallin B Chain / drug effects
  • alpha-Crystallin B Chain / metabolism

Substances

  • CRYAB protein, human
  • Fatty Acids
  • Fatty Acids, Omega-3
  • Prostaglandins
  • alpha-Crystallin B Chain
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • Dinoprostone