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.
Highlights
Lung cancer is one of the most common cancers and causes more than 1.37 million deaths worldwide
lactate dehydrogenase A (LDH-A) inhibition resulted in ATP reduction and reactive oxygen species (ROS) burst in cancer cells, which lead to apoptosis and G2/M arrest in H1395 cells
LDH-A has been widely investigated as an antitumor target in previous studies, and accumulating evidence indicates that inhibition of LDH-A induces apoptosis though mitochondrial pathway mediated by oxidative stress[13, 15, 17, 18]
Summary
Lung cancer is one of the most common cancers and causes more than 1.37 million deaths worldwide. The incidence of lung cancer is still on the rise, due to the prevalence of smoking and air pollution, especially in the developing countries[1]. There is an urgent need to develop novel strategies to treat lung cancer. It is noticed long before that cancer cells have higher uptake of glucose and more dependent on the anerobic glycolysis to produce ATP, the phenomenon is known as “Warburg effect” [3]. In recent years, targeting energy metabolism has returned to the battlefield of fighting against cancer, more details and molecular mechanisms involved in the “Warburg effect” are increasingly discovered, which make us better understand the characteristics of cancer cells, and provide the Achilles’ heel to kill them[4]
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