Targeting lactate dehydrogenase a improves radiotherapy efficacy in non-small cell lung cancer: from bedside to bench

Abstract

Background Lactate dehydrogenase A (LDHA) is overexpressed and associated with poor prognosis in many kinds of cancer. In the current study, we evaluated the prognostic value of LDHA expression in non-small cell lung cancer (NSCLC), and tested whether LDHA inhibition might improve radiotherapy efficacy in NSCLC. Methods LDHA expression was investigated in NSCLC patients, using online database and further verified by immunohistochemistry. The prognostic value of LDHA was evaluated using Kaplan–Meier plotter database. In vitro, two NSCLC cell lines were pretreated with oxamate, an inhibitor of LDHA, and colony formation method was performed to determine cellular radiosensitivity. Comet assay was used to detect DNA damage after irradiation. Flow cytometry was applied to test cell cycle progression and apoptosis, and monodansylcadaverine (MDC) staining was used to examine cell autophagy. Results Both mRNA and protein levels of LDHA expression were up-regulated in NSCLC tissues. High LDHA expression was a poor prognostic factor and associated with radioresistance in NSCLC patients. LDHA inhibition by oxamate remarkably increased radiosensitivity in both A549 and H1975 cancer cells, and enhanced ionizing radiation (IR)-induced apoptosis and autophagy, accompanied by cell cycle distribution alternations. Furthermore, LDHA inhibition induced reactive oxygen species (ROS) accumulation and cellular ATP depletion, which might increase DNA injury and hinder DNA repair activity. Conclusions Our study suggests that inhibition of LDHA may be a potential strategy to improve radiotherapy efficacy in NSCLC patients, which needs to be further tested by clinical trials.

Serum lactate dehydrogenase predicts brain metastasis and survival in limited-stage small cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation

“…Our previous study [26] has revealed that oxamate, an inhibitor of LDH-A, signi cantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal cells. LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells, which lead to apoptosis and G2/M arrest and increase radiosensitivity in NSCLC cells [27].…”

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

“…The analyses of LDHA and PDK1 in situ protein expression also showed association with poor survival and therapy resistance in many malignancies (colon, breast, uterine, pancreas, lung, renal, gastric cancers, CNS malignancies, etc.). Considering the increasing serum lactate level of end-stage cachexia patients, these observations are not surprising [196][197][198][199][200][201].…”

Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor–resistant pancreatic ductal adenocarcinoma

“…The overexpression of the metabolic enzyme LDHA is necessary for tumor growth and progression (6)(7)(8)(9)(10)(13)(14)(15). LDHA typically exists as a tetramer (LDH-5) and functions primarily to interconvert pyruvate to lactate and transform NADH to NAD+.…”

“…Notably, a number of enzymes and transporters that promote glycolysis and glucose metabolism are overexpressed in cancer cells relative to normal cells (4,5). One such enzyme, lactic acid dehydrogenase A (LDHA), is known to be overexpressed in several cancer types and associated with poor prognosis (6)(7)(8)(9)(10).…”