A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose
| Autor: | Alireza Delfarah, Philip S. Phung, James H. Joly, Sydney Parrish, Nicholas A. Graham |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Programmed cell death Amino Acid Transport System y+ Cell Survival Synthetic Drugs Glutamic Acid Pharmacology Carbohydrate metabolism SLC7A11 Biochemistry Antiporters 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols Humans Cysteine Molecular Biology Glucose Transporter Type 1 Cell Death biology Cell Biology Glutathione Glucose Metabolism 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer cell Metabolome biology.protein Cystine GLUT1 Reactive Oxygen Species Dimerization Oxidation-Reduction NADP Intracellular |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X 0021-9258 |
| DOI: | 10.1074/jbc.ra119.011471 |
| Popis: | Metabolic reprogramming in cancer cells can increase their dependence on metabolic substrates such as glucose. As such, the vulnerability of cancer cells to glucose deprivation creates an attractive opportunity for therapeutic intervention. Because it is not possible to starve tumors of glucosein vivo, here we sought to identify the mechanisms in glucose deprivation–induced cancer cell death and then designed inhibitor combinations to mimic glucose deprivation–induced cell death. Using metabolomic profiling, we found that cells undergoing glucose deprivation–induced cell death exhibited dramatic accumulation of intracellularl-cysteine and its oxidized dimer,l-cystine, and depletion of the antioxidant GSH. Building on this observation, we show that glucose deprivation–induced cell death is driven not by the lack of glucose, but rather byl-cystine import. Following glucose deprivation, the import ofl-cystine and its subsequent reduction tol-cysteine depleted both NADPH and GSH pools, thereby allowing toxic accumulation of reactive oxygen species. Consistent with this model, we found that the glutamate/cystine antiporter (xCT) is required for increased sensitivity to glucose deprivation. We searched for glycolytic enzymes whose expression is essential for the survival of cancer cells with high xCT expression and identified glucose transporter type 1 (GLUT1). Testing a drug combination that co-targeted GLUT1 and GSH synthesis, we found that this combination induces synthetic lethal cell death in high xCT-expressing cell lines susceptible to glucose deprivation. These results indicate that co-targeting GLUT1 and GSH synthesis may offer a potential therapeutic approach for targeting tumors dependent on glucose for survival. |
| Databáze: | OpenAIRE |
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