The Beta-Hydroxybutyrate Suppresses the Migration of Glioma Cells by Inhibition of NLRP3 Inflammasome

Cell Mol Neurobiol. 2018 Nov;38(8):1479-1489. doi: 10.1007/s10571-018-0617-2. Epub 2018 Sep 14.

Abstract

Activation of inflammasome leads to the formation of an inflammatory microenvironment which plays an important role in the process of cancer development. Beta-hydroxybutyrate (BHB) is a ketone body that has recently been reported to exert anti-inflammatory effects via inhibition of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Here, we investigated the potential influence of BHB on the in vitro migration of C6 glioma cells and the activation of NLRP3 inflammasome. Our results indicated that administration of BHB suppressed C6 cells migration and NLRP3 inflammasome activation, reducing the levels of activated cysteinyl aspartate-specific proteinase 1 (caspase-1) and mature Interleukin 1β (IL-1β). Fully activation of NLRP3 inflammasome was induced by lipopolysaccharide (LPS) prime plus adenosine triphosphate (ATP) stimulation in C6 cells, which promoted in vitro migration of C6 cell. BHB also counteracted the LPS/ATP-promoted cell migration by suppressing the activation of caspase-1 and the maturation of IL-1β. The enhancement of phospho-signal transducer and activator of transcription 3 (p-STAT3), degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) as well as the overexpression of fibroblast growth factor 2 (FGF2) resulting from LPS/ATP treatment, and subsequent IL-1β maturation could also be compensated by BHB. Our results suggested that BHB inhibits the activation of NLRP3 inflammasome in C6 glioma cells and consequently suppressed the C6 cell migration. These findings also implicated that by inhibiting NLRP3 inflammasome, BHB reduced the inflammatory microenvironment which provided ancillary therapeutic benefits for the intervention of glioma.

Keywords: Beta-hydroxybutyrate; Glioma; Migration; NLRP3 inflammasome.

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology*
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Survival / drug effects
  • Glioma / metabolism*
  • Glioma / pathology*
  • Inflammasomes / metabolism*
  • Lipopolysaccharides / pharmacology
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Pertussis Toxin / pharmacology
  • Rats

Substances

  • Inflammasomes
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Adenosine Triphosphate
  • Pertussis Toxin
  • 3-Hydroxybutyric Acid