Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Blood. 2016 Aug 4;128(5):667-79. doi: 10.1182/blood-2016-01-690743. Epub 2016 Jun 6.

Abstract

The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Transport System ASC / metabolism
  • Ammonium Compounds / metabolism
  • Animals
  • Asparaginase / metabolism
  • Biological Transport
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Glutamate-Ammonia Ligase / metabolism
  • Glutaminase / metabolism
  • Glutamine / metabolism*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Minor Histocompatibility Antigens / metabolism
  • Molecular Targeted Therapy*
  • Monoclonal Gammopathy of Undetermined Significance / pathology
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • Syndecan-1 / metabolism

Substances

  • Amino Acid Transport System ASC
  • Ammonium Compounds
  • Membrane Transport Proteins
  • Minor Histocompatibility Antigens
  • SLC1A5 protein, human
  • Syndecan-1
  • Glutamine
  • Asparaginase
  • Glutaminase
  • Glutamate-Ammonia Ligase