Enhancing lobaplatin sensitivity in lung adenocarcinoma through inhibiting LDHA-targeted metabolic pathways
Siyu Yuan1, Wenjie Ou2, Xuguang Mi3
1Department of Clinical Nutrition, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Background And Objective:
Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), is associated with high incidence and mortality rates. Effective treatment options are limited due to the frequent development of multidrug resistance, making it crucial to identify new therapeutic targets and sensitizing agents. This study investigates the role of Lactate dehydrogenase A (LDHA) in enhancing the chemotherapy sensitivity of Lobaplatin (LBP) in LUAD.
Methods:
Bioinformatics analyses were performed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to assess LDHA expression in LUAD tissues. LUAD cell lines A549 and NCL-H1975 were treated with siRNA targeting LDHA and the small molecule inhibitor Oxamate. We measured changes in lactate production, ATP levels, NAD+ and pyruvate levels, and assessed cell viability. The chemotherapy sensitivity to Lobaplatin was evaluated, and key signaling pathways related to chemotherapy resistance were analyzed.
Results:
The inhibition of LDHA resulted in a significant reduction in lactate production and ATP levels, along with an increase in NAD+ and pyruvate levels. These metabolic alterations led to decreased cell viability and enhanced sensitivity to Lobaplatin. The study identified the PI3K/AKT signaling pathway as a critical mediator of this enhanced sensitivity, with reduced phosphorylation of AKT observed upon LDHA inhibition. Furthermore, the combination of LDHA inhibition and Lobaplatin treatment demonstrated a synergistic effect, significantly inhibiting tumor growth and highlighting the potential of LDHA as a therapeutic target to overcome drug resistance in LUAD.
Conclusion:
Targeting LDHA and disrupting lactate metabolism and its signaling pathways can effectively enhance the sensitivity of LUAD to Lobaplatin, providing a promising approach to overcoming multidrug resistance. These findings offer valuable insights into developing new treatment strategies for lung adenocarcinoma, emphasizing the role of metabolic pathways in cancer therapy.
Insights
Targeting Lactate dehydrogenase A (LDHA) in lung adenocarcinoma (LUAD) enhances sensitivity to Lobaplatin (LBP) chemotherapy. Inhibiting LDHA disrupts cancer metabolism and overcomes multidrug resistance, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) presents significant therapeutic challenges due to high mortality and multidrug resistance.
- Identifying novel targets to enhance chemotherapy efficacy is critical for improving patient outcomes in LUAD.
- Lactate dehydrogenase A (LDHA) is implicated in cancer metabolism and drug resistance.
Purpose of the Study:
- To investigate the role of LDHA in modulating chemotherapy sensitivity to Lobaplatin (LBP) in LUAD.
- To explore LDHA as a potential therapeutic target for overcoming drug resistance in LUAD.
Main Methods:
- Bioinformatic analysis of TCGA and GEO datasets to evaluate LDHA expression in LUAD.
- In vitro experiments using LUAD cell lines with LDHA inhibition (siRNA, Oxamate) to assess metabolic changes and cell viability.
- Evaluation of LBP sensitivity and analysis of key signaling pathways, including PI3K/AKT.
Main Results:
- LDHA inhibition significantly reduced lactate and ATP levels, increasing NAD+ and pyruvate.
- Metabolic alterations upon LDHA inhibition led to decreased cell viability and enhanced LBP sensitivity.
- The PI3K/AKT pathway was identified as a mediator, with LDHA inhibition reducing AKT phosphorylation. Combination therapy showed synergistic tumor growth inhibition.
Conclusions:
- Targeting LDHA effectively enhances LUAD sensitivity to LBP by disrupting lactate metabolism and associated signaling pathways.
- LDHA inhibition presents a promising strategy to overcome multidrug resistance in LUAD.
- Metabolic pathway modulation offers a novel therapeutic avenue for lung adenocarcinoma treatment.
