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Lactate dehydrogenase A promotes nasopharyngeal carcinoma progression through the TAK1/NF-κB Axis

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Abstract

Background

Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates in the nasopharyngeal mucosa and is common in China and Southeast Asian countries. Cancer cells reprogram glycolytic metabolism to promote their growth, survival and metastasis. Glycolysis plays an important role in NPC development, but the underlying mechanisms remain incompletely elucidated. Lactate dehydrogenase A (LDHA) is a crucial glycolytic enzyme, catalyzing the last step of glycolysis. This study aims to investigate the exact role of LDHA, which catalyzes the conversion of pyruvate into lactate, in NPC development.

Methods and results

The western blot and immunohistochemical (IHC) results indicated that LDHA was significantly upregulated in NPC cells and clinical samples. LDHA knockdown by shRNA significantly inhibited NPC cell proliferation and invasion. Further knockdown of LDHA dramatically weakened the tumorigenicity of NPC cells in vivo. Mechanistic studies showed that LDHA activated TGF-β-activated kinase 1 (TAK1) and subsequent nuclear factor κB (NF-κB) signaling to promote NPC cell proliferation and invasion. Exogenous lactate supplementation restored NPC cell proliferation and invasion inhibited by LDHA knockdown, and this restorative effect was reversed by NF-κB inhibitor (BAY 11-7082) or TAK1 inhibitor (5Z-7-oxozeaenol) treatment. Moreover, clinical sample analyses showed that LDHA expression was positively correlated with TAK1 Thr187 phosphorylation and poor prognosis.

Conclusions

Our results suggest that LDHA and its major metabolite lactate drive NPC progression by regulating TAK1 and its downstream NF-κB signaling, which could become a therapeutic target in NPC.

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Data Availability

(ADM)

The data that support the findings of the study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the Guangzhou Municipal Science and Technology Bureau-the First Affiliated Hospital of Guangzhou Medical University Joint Project (2024A03J1155), Guangdong Provincial Department of Science and Technology (2018A030313525), the State Key Laboratory of Respiratory Disease, (SKLRD-Z-202215), the High Level Project of the People’s Hospital of Yangjiang (G2021001), the National Natural Science Foundation of China (81972163).

Author information

Author notes

  1. Yingzi Li, Lanfang Chen and Qiaochong Zheng contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Respiratory Disease at People’s Hospital of Yangjiang, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Yingzi Li, Lanfang Chen, Guanxin Liu & Tao Chen

  2. Yangjiang Key Laboratory of Respiratory Disease, Department of Respiratory Medicine, People’s Hospital of Yangjiang, Yangjiang, 529500, Guangdong, China

    Yingzi Li, Qiaochong Zheng & Tao Chen

  3. Clinical Research Lab Center, Guizhou Provincial People’s Hospital, Guizhou University Medical College, Guiyang, 550025, Guizhou, China

    Mengjiao Wang

  4. State Key Laboratory of Respiratory Disease, Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China

    Shupei Wei

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  1. Yingzi Li
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Contributions

This study was conceived by T.C.; T.C., S.W. and Y. L. designed the study; L.Y., L.C. and Q.Z. performed the experiments and analyzed the data with the assistance of G.L., M.W., and L.C.; Y.L., S.W. and T.C. wrote the paper with comments from all authors.

Corresponding authors

Correspondence to Shupei Wei or Tao Chen.

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Ethical approval of research involving animals: All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and the study is reported in accordance with ARRIVE guidelines. Research involving human clinical tissues: All procedures performed in these studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards; informed consent was obtained from all patients and/or their legal guardian(s). All experimental protocols were approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University.

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Written informed consent for publication was obtained from all the authors. Informed consent from all subjects and/or their legal guardian(s) for “publication of identifying information/images in an online open-access publication” was not applicable, as no identifying information/images of human participants are included in the manuscript.

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Li, Y., Chen, L., Zheng, Q. et al. Lactate dehydrogenase A promotes nasopharyngeal carcinoma progression through the TAK1/NF-κB Axis. Mol Biol Rep 51, 152 (2024). https://doi.org/10.1007/s11033-023-09130-9

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