A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo
| Autor: | Juan Ding, Huzoor Akbar, Yanyan Cao, Shiyong Wu, Lingying Tong, Weihe Zhang, Yanrong Qian, Xiaozhuo Chen, Stephen C. Bergmeier, Robert B. Colvin, Jennifer V. Hines, Liu Yi |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Mice Nude Antineoplastic Agents Biology Models Biological Mice Cell Line Tumor Neoplasms Hydroxybenzoates Animals Humans Glycolysis Cell Proliferation Glucose Transporter Type 1 Cell growth Glucose transporter Biological Transport Cell Cycle Checkpoints Warburg effect Tumor Burden Cell biology Molecular Docking Simulation Glucose Oncology Cancer cell biology.protein GLUT1 Intracellular Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics. 11:1672-1682 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation–like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor–treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism. Mol Cancer Ther; 11(8); 1672–82. ©2012 AACR. |
| Databáze: | OpenAIRE |
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