Oncotarget

Research Papers:

Different effects of LDH-A inhibition by oxamate in non-small cell lung cancer cells

Yang Yang, Dan Su, Lin Zhao, Dan Zhang, Jiaying Xu, Jianmei Wan, Saijun Fan and Ming Chen _

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Oncotarget. 2014; 5:11886-11896. https://doi.org/10.18632/oncotarget.2620

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Abstract

Yang Yang1,2, Dan Su3, Lin Zhao2, Dan Zhang3, Jiaying Xu2, Jianmei Wan2, Saijun Fan2,4 and Ming Chen1

1 Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China

2 School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China

3 Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China

4 Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

Correspondence:

Ming Chen, email:

Saijun Fan, email:

Keywords: lactate dehydrogenase A, Warburg effect, G0/G1 arrest, autophagy, apoptosis, Akt/mTOR

Received: September 23, 2014 Accepted: October 22, 2014 Published: October 22, 2014

Abstract

Higher rate of glycolysis has been long observed in cancer cells, as a vital enzyme in glycolysis, lactate dehydrogenase A (LDH-A) has been shown with great potential as an anti-cancer target. Accumulating evidence indicates that inhibition of LDH-A induces apoptosis mediated by oxidative stress in cancer cells. To date, it’s still unclear that whether autophagy can be induced by LDH-A inhibition. Here, we investigated the effects of oxamate, one classic inhibitor of LDH-A in non-small cell lung cancer (NSCLC) cells as well as normal lung epithelial cells. The results showed that oxamate significantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal cells. As previous studies reported, LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells, which lead to apoptosis and G2/M arrest in H1395 cells. However, when being exposed to oxamate, A549 cells underwent autophagy as a protective mechanism against apoptosis. Furthermore, we found evidence that LDH-A inhibition induced G0/G1 arrest dependent on the activation of GSK-3β in A549 cells. Taken together, our results provide useful clues for targeting LDH-A in NSCLC treatment and shed light on the discovery of molecular predictors for the sensitivity of LDH-A inhibitors.


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