Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma
| Autor: | Xin Cao, Heng Li, Danna Tu, Jian-Xin Jiang, Shan Gao, Jin-Bin You, Xiaoqin Zhou |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lactate dehydrogenase A Naphthalenes Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Neoplasm Invasiveness Glycolysis Gene Silencing Child education Cell Proliferation Pharmacology Osteosarcoma Gene knockdown education.field_of_study L-Lactate Dehydrogenase Cell growth General Medicine Warburg effect Isoenzymes 030104 developmental biology Anaerobic glycolysis Tumor progression 030220 oncology & carcinogenesis Disease Progression Cancer research Lactate Dehydrogenase 5 Carcinogenesis |
| Zdroj: | Biomedicine & Pharmacotherapy. 81:388-393 |
| ISSN: | 0753-3322 |
| Popis: | Reprogrammed energy metabolism is an emerging hallmark of cancer. Lactate dehydrogenase A (LDHA), a key enzyme involved in anaerobic glycolysis, is frequently deregulated in human malignancies. However, limited knowledge is known about its roles in the progression of osteosarcoma (OS). In this study, we found that LDHA is commonly upregulated in four OS cell lines compared with the normal osteoblast cells (hFOB1.19). Treatment with FX11, a specific inhibitor of LDHA, significantly reduced LDHA activity, and inhibited cell proliferation and invasive potential in a dose dependent manner. Genetic silencing of LDHA resulted in a decreased lactate level in the culture medium, reduced cell viability and decreased cell invasion ability. Meanwhile, silencing of LDHA also compromised tumorigenesis in vivo. Furthermore, knockdown of LDHA remarkably reduced extracellular acidification rate (ECAR) as well as glucose consumption. In the presence of 2-DG, a glycolysis inhibitor, LDHA-mediated cell proliferation and invasion were completely blocked, indicating the oncogenic activities of LDHA may dependent on Warburg effect. Finally, pharmacological inhibition of c-Myc or HIF1α significantly attenuated LDHA expression. Taken together, upregulated LDHA facilitates tumor progression of OS and might be a potential target for OS treatment. |
| Databáze: | OpenAIRE |
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