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Background
LDHA is overexpressed in many kinds of cancer, and associated with poor prognosis. 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 mRNA 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 autophagy was examined by monodansylcadaverin (MDC) staining.
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 inhibition of LDHA may be a potential strategy to improve radiotherapy efficacy in NSCLC patients, which needs to be further tested by clinical trials.
Keywords
LDHA, NSCLC, radiosensitivity, DNA repair, ROS, apoptosis
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CURRENT STATUS: Published
View the published article at Journal of Translational Medicine.
Version 1
Posted 22 Feb, 2021
No community comments so far
Reviewer #3 agreed
On 23 Feb, 2021
Reviewer #2 agreed
On 20 Feb, 2021
Review #2 received
Received 20 Feb, 2021
Reviews received
Received 15 Feb, 2021
Reviewer #1 agreed
On 15 Feb, 2021
Reviewers invited
Invitations sent on 15 Feb, 2021
Editor assigned
On 09 Feb, 2021
Submission checks complete
On 09 Feb, 2021
Editor invited
On 09 Feb, 2021
First submitted
On 08 Feb, 2021
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Subject Areas
Translational Medicine
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
See the published version of this preprint at Journal of Translational Medicine.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Journal of Translational Medicine.
Version 1
Posted 22 Feb, 2021
No community comments so far
Reviewer #3 agreed
On 23 Feb, 2021
Reviewer #2 agreed
On 20 Feb, 2021
Review #2 received
Received 20 Feb, 2021
Reviews received
Received 15 Feb, 2021
Reviewer #1 agreed
On 15 Feb, 2021
Reviewers invited
Invitations sent on 15 Feb, 2021
Editor assigned
On 09 Feb, 2021
Submission checks complete
On 09 Feb, 2021
Editor invited
On 09 Feb, 2021
First submitted
On 08 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Translational Medicine.
Background
LDHA is overexpressed in many kinds of cancer, and associated with poor prognosis. 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 mRNA 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 autophagy was examined by monodansylcadaverin (MDC) staining.
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 inhibition of LDHA may be a potential strategy to improve radiotherapy efficacy in NSCLC patients, which needs to be further tested by clinical trials.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
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