Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells.
An elevated rate of glucose consumption and the dependency on aerobic glycolysis for ATP generation have long been observed in cancer cells, a phenomenon known as the Warburg effect. the altered energy metabolism in cancer cells provides an attractive opportunity for developing novel cancer therapeutic strategies. Lactate dehydrogenase (LDH), which catalyzes the transformation of pyruvate to lactate, plays a vital role in the process of glycolysis. It has been reported that the level of LDH-A expression is increased both in head and neck cancer cells and in the blood serum of nasopharyngeal carcinoma (NPC) patients, and is associated with poor prognosis. However, the effect of LDH-A inhibition on NPC cells remains unknown. Here, in the present study, we found that oxamate, a classical inhibitor of LDH-A, suppressed cell proliferation in a dose- and time-dependent manner both in CNE-1 and CNE-2 cells, two NPC cancer cell lines. LDH inhibition by oxamate induced G2/M cell cycle arrest via downregulation of the CDK1/cyclin B1 pathway and promoted apoptosis through enhancement of mitochondrial ROS generation. N-acetylcysteine, a specific scavenger of ROS, significantly blocked the growth inhibition effect induced by oxamate. We also identified that oxamate increased sensitivity to ionizing radiation in the two NPC cancer cell lines. Furthermore, we verified similar results in tumor xenograft models. collectively, these results suggest that LDH-A may serve as a promising therapeutic target for NPC treatment.
Department of Radiation Oncology, The First Affiliated Hospital, Soochow University, Suzhou, P.R. China.
Xiaoming
X
Zhai
Yang
Y
Yang
Jianmei
J
Wan
Ran
R
Zhu
Yiwei
Y
Wu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002277:Carcinoma; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000080864:Lactate Dehydrogenase 5; D051379:Mice; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D009930:Organic Chemicals / Q000008:administration & dosage; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C534699:CCNB1 protein, human; D056744:Cyclin B1; D007527:Isoenzymes; D009930:Organic Chemicals; D017382:Reactive Oxygen Species; C048603:oxamate (repellent); D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D016203:CDC2 Protein Kinase