Glutamine synthetase functions as a negative growth regulator in glioma

J Neurooncol. 2013 Aug;114(1):59-69. doi: 10.1007/s11060-013-1168-5. Epub 2013 Jun 19.

Abstract

Our recent study demonstrated that glutamine synthetase (GS) may not only serve as a glutamate-converting enzyme in glial cells, but may also function as a regulator of astrocyte migration after injury. In this report, we showed that GS expression increased in cultured rat C6 glioma cells that underwent long-term serially propagation. The stable overexpression of GS in C6 glioma cells resulted in growth arrest and motility suppression; however the stable knockdown of GS resulted in motility enhancement. In correlation with cell aggregation, N-cadherin levels increased at sites of cell-cell contact in C6 cells overexpressing GS, and decreased in C6 cells with stable GS knockdown; total N-cadherin expression levels remained unchanged in these cells. In addition, levels of p21, a potent cyclin-dependent kinase inhibitor, increased, while cyclin D1 levels decreased in C6 cells overexpressing GS. Our additional studies showed that N-cadherin-mediated cell-cell contacts were implicated in GS-induced cell growth arrest and impairment of cell migration, as evidenced by the inhibition of GS on cell growth and motility by the neutralizing anti-N-cadherin monoclonal antibody (GC-4 mAb). Collectively, these observations suggest a novel mechanism of growth regulation by GS that involves N-cadherin mediated cell-cell contact.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / physiology
  • Cell Communication / drug effects
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Movement / physiology*
  • Cell Proliferation* / drug effects
  • Colony-Forming Units Assay
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Glioma / pathology
  • Glutamate-Ammonia Ligase / genetics
  • Glutamate-Ammonia Ligase / immunology
  • Glutamate-Ammonia Ligase / metabolism*
  • Glutamine / pharmacology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Time Factors
  • Wound Healing / drug effects
  • Wound Healing / physiology

Substances

  • Glial Fibrillary Acidic Protein
  • Ki-67 Antigen
  • RNA, Small Interfering
  • Glutamine
  • Green Fluorescent Proteins
  • Glutamate-Ammonia Ligase