Title:Glutaminase Isoenzymes as Key Regulators in Metabolic and Oxidative Stress Against Cancer
Volume: 13
Issue: 4
Author(s): J.M. Mates, J.A. Segura, M. Martin-Rufian, J.A. Campos-Sandoval, F.J. Alonso and J. Marquez
Affiliation:
Keywords:
Cancer, c-Myc, glutaminase, glutamine, metabolism, p53, ROS, Warburg effect
Abstract: Cancer cells require a robust supply of reduced nitrogen to produce nucleotides, non-essential
amino acids and a high cellular redox activity. Glutamine provides a major substrate for respiration as well as
nitrogen for the production of proteins, hexosamines, and macromolecules. Therefore, glutamine is one of key
molecules in cancer metabolism during cell proliferation. The notion of targeting glutamine metabolism in
cancer, originally rationalized by the number of pathways fed by this nutrient, has been reinforced by more
recent studies demonstrating that its metabolism is regulated by oncogenes. Glutamine can exert its effects by
modulating redox homeostasis, bioenergetics, nitrogen balance or other functions, including by being a
precursor of glutathione, the major nonenzymatic cellular antioxidant. Glutaminase (GA) is the first enzyme that
converts glutamine to glutamate, which is in turn converted to alpha-ketoglutarate for further metabolism in the
tricarboxylic acid cycle. Different GA isoforms in mammals are encoded by two genes, Gls and Gls2. As each
enzymatic form of GA has distinct kinetic and molecular characteristics, it has been speculated that the
differential regulation of GA isoforms may reflect distinct functions or requirements in different tissues or cell
states. GA encoded by Gls gene (GLS) has been demonstrated to be regulated by oncogenes and to support
tumor cell growth. GA encoded by Gls2 gene (GLS2) reduces cellular sensitivity to reactive oxygen speciesassociated
apoptosis possibly through glutathione-dependent antioxidant defense, and therefore to behave
more like a tumor suppressor. Thus, modulation of GA function may be a new therapeutic target for cancer
treatment.
