L-Asparaginase and Inhibitors of Glutamine Synthetase Disclose Glutamine Addiction of β-Catenin-Mutated Human Hepatocellular Carcinoma Cells
| Autor: | Zerbini A, Uggeri J, Saverio Tardito, Ovidio Bussolati, Gabriele Missale, Da Ros F, Dall'Asta, Chiu M |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Carcinoma Hepatocellular Glutamine Cell Antineoplastic Agents Apoptosis Biology Glutamate-Ammonia Ligase Cell Line Tumor Glutamine synthetase Drug Discovery Autophagy medicine Asparaginase Humans Gene Silencing Molecular Targeted Therapy Enzyme Inhibitors Phosphorylation beta Catenin PI3K/AKT/mTOR pathway Cell Proliferation Pharmacology chemistry.chemical_classification Liver Neoplasms Molecular biology Recombinant Proteins digestive system diseases Neoplasm Proteins Amino acid Eukaryotic Initiation Factor-2B Enzyme medicine.anatomical_structure Oncology Biochemistry chemistry Drug Resistance Neoplasm Cell culture Mutant Proteins Protein Processing Post-Translational |
| Zdroj: | Current Cancer Drug Targets. 11:929-943 |
| ISSN: | 1568-0096 |
| DOI: | 10.2174/156800911797264725 |
| Popis: | Selected oncogenic mutations support unregulated growth enhancing glutamine availability but increasing the dependence of tumor cells on the amino acid. Data from literature indicate that a subset of HepatoCellular Carcinomas (HCC) is characterized by mutations of β-catenin and overexpression of Glutamine Synthetase (GS). To assess if this phenotype may constitute an example of glutamine addiction, we treated four human HCC lines with the enzyme L-Asparaginase (ASNase), a glutaminolytic drug. ASNase had a significant antiproliferative effect only in the β-catenin mutated HepG2 cells, which were partially rescued by the anaplerotic intermediates pyruvate and α-ketoglutarate. The enzyme severely depleted cell glutamine, caused eIF2α phosphorylation, inhibited mTOR activity, and increased autophagy in both HepG2 and in the β-catenin wild type cell line Huh-7. When used with ASNase, the GS inhibitor methionine sulfoximine (MSO) emptied cell glutamine pool, arresting proliferation in ASNase-insensitive Huh-7 cells and activating caspase-3 and apoptosis in HepG2 cells. Compared with Huh-7 cells, HepG2 cells accumulated much higher levels of glutamine and MSO, due to the higher expression and activity of SNAT2, a concentrative transporter for neutral amino acids, but were much more sensitive to glutamine withdrawal from the medium. In the presence of ASNase, MSO caused a paradoxical maintenance of rapamycin-sensitive mTOR activity in both HepG2 and Huh-7 cells. β-catenin silencing lowered ASNase sensitivity of HepG2 cells and of Huh-6 cells, another β-catenin-mutated cell line, which also exhibited high sensitivity to ASNase. Thus, β-catenin mutated HCC cells are more sensitive to glutamine depletion and accumulate higher levels of GS inhibitors. These results indicate that glutamine deprivation may constitute a targeted therapy for β-catenin-mutated HCC cells addicted to the amino acid. |
| Databáze: | OpenAIRE |
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