Metabolic Vulnerabilities in Endometrial Cancer
| Autor: | Kyle L. Hoehn, W. Baker, Jenny D.Y. Chow, Kristen A. Atkins, Johnathan M. Lancaster, Susan C. Modesitt, Jose L. Tomsig, Kelle H. Moley, Douglas C. Marchion, Ivan K. H. Poon, Kodi S. Ravichandran, Frances L. Byrne, Jill K. Slack-Davis, Marin E. Healy |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
medicine.medical_specialty Programmed cell death Cell Survival Pyruvate Kinase Glucose Transport Proteins Facilitative Mice Nude Antineoplastic Agents Biology Endometrium Necrosis Downregulation and upregulation Cell Line Tumor Hexokinase Internal medicine medicine Animals Humans Coenzyme A Glycolysis Molecular Targeted Therapy Pyruvates Lipogenesis Endometrial cancer Glucose transporter Cancer Middle Aged medicine.disease Xenograft Model Antitumor Assays Endometrial Neoplasms Tumor Burden Endocrinology Oncology Case-Control Studies Female Reactive Oxygen Species Pyruvate kinase |
| Zdroj: | Cancer Research. 74:5832-5845 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts Cancer Res; 74(20); 5832–45. ©2014 AACR. |
| Databáze: | OpenAIRE |
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