Journal
JOURNAL OF MOLECULAR MEDICINE-JMM
Volume 92, Issue 3, Pages 277-290Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00109-013-1105-2
Keywords
Apoptosis.; Cancer.; Glioma.; Glutaminase.; Glutathione.; ROS
Funding
- Ministerio de Educacion of Spain [PHB2010-0014-PC]
- Ministerio de Ciencia y Tecnologia of Spain [SAF2010-17573]
- Junta de Andalucia, Spain [CVI-6656, PI-0825-2010]
- RTA RETICS network from the Spanish Health Institute Carlos III, Spain [RD06/1012]
- NIH [R01 CA157996]
- Cancer Prevention and Research Institute of Texas [HIRP100437, RP101243]
- Robert A. Welch Foundation [I-1733]
- Damon-Runyon Cancer Research Foundation
- Ministry of Science and Higher Education (National Science Centre) [NN401 039238]
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Mitochondrial glutaminase (GA) plays an essential role in cancer cell metabolism, contributing to biosynthesis, bioenergetics, and redox balance. Humans contain several GA isozymes encoded by the GLS and GLS2 genes, but the specific roles of each in cancer metabolism are still unclear. In this study, glioma SFxL and LN229 cells with silenced isoenzyme glutaminase KGA (encoded by GLS) showed lower survival ratios and a reduced GSH-dependent antioxidant capacity. These GLS-silenced cells also demonstrated induction of apoptosis indicated by enhanced annexin V binding capacity and caspase 3 activity. GLS silencing was associated with decreased mitochondrial membrane potential (triangle psi m) (JC-1 dye test), indicating that apoptosis was mediated by mitochondrial dysfunction. Similar observations were made in T98 glioma cells overexpressing glutaminase isoenzyme GAB, encoded by GLS2, though some characteristics (GSH/ GSSG ratio) were different in the differently treated cell lines. Thus, control of GA isoenzyme expression may prove to be a key tool to alter both metabolic and oxidative stress in cancer therapy. Interestingly, reactive oxygen species (ROS) generation by treatment with oxidizing agents: arsenic trioxide or hydrogen peroxide, synergizes with either KGA silencing or GAB overexpression to suppress malignant properties of glioma cells, including the reduction of cellular motility. Of note, negative modulation of GLS isoforms orGAB overexpression evoked lower c-myc and bcl-2 expression, as well as higher pro-apoptotic bid expression. Combination of modulation of GA expression and treatment with oxidizing agents may become a therapeutic strategy for intractable cancers and provides a multi-angle evaluation system for anti-glioma preclinical investigations.
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