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

Yang Yang,Wumin Dai,Yongling Ji,Xia Zhou,Xianghui Du,Guoqin Qiu,Mengyuan Chen,Yu Chong

doi:10.1186/s12967-021-02825-2

Abstract

BackgroundLactate 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.MethodsLDHA 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.ResultsBoth 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.ConclusionsOur 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.

Highlights

Lactate dehydrogenase A (LDHA) is overexpressed and associated with poor prognosis in many kinds of cancer
We previously reported that diverse biological effects were observed in non-small cell lung cancer (NSCLC) cells induced by LDHA inhibition, including autophagy or apoptosis, accompanied with different cell cycle distribution alternations [16]
The association among LDHA mRNA expression level and survival of NSCLC patients was investigated by data mining in the Kaplan–Meier plotter database, an online database integrating gene expression and survival information simultaneously download from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) [18]

Summary

Introduction

Lactate dehydrogenase A (LDHA) is overexpressed and associated with poor prognosis in many kinds of cancer. Radiotherapy plays a vital role in lung cancer treatment, almost three quarters of all lung cancer patients need to. There is still an urgent need to seek for novel strategies to enhance radiotherapy efficiency in NSCLC patients. As a key enzyme evolved in glycolysis, LDHA has been reported to be up-regulated and greatly associated with poor prognosis in many kinds of cancer [5,6,7,8,9]. Accumulating evidence indicates that LDHA inhibition exhibits promising anti-cancer effects through disrupting cellular energy metabolism, and synergistically enhances the efficacy of other therapeutic regimens, including chemotherapy [10], radiotherapy [11, 12] and target drugs [13,14,15]. The role of LDHA in regulating radiosensitivity of NSCLC has not been elucidated up to now

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