July 13, 2024

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Lactic Acid: The Unexpected Ally of Cancer Cells in DNA Repair and Chemoresistance

Lactic Acid: The Unexpected Ally of Cancer Cells in DNA Repair and Chemoresistance



Lactic Acid: The Unexpected Ally of Cancer Cells in DNA Repair and Chemoresistance

Recent research reveals that lactic acid aids cancer cells in repairing DNA damage, helping them resist radiotherapy and chemotherapy. Tumors, which are acidic by nature, produce lactic acid through aerobic glycolysis.

The Role of Lactic Acid in Cancer Progression

In recent years, extensive foundational research has shown that tumor-derived lactic acid can be described in four words: harmful and pervasive.

  • Tumor Protein Deactivation: Just over two months ago, researchers discovered that lactic acid can deactivate the tumor suppressor protein p53 through lactylation, thereby promoting cancer progression.

  • Macrophage Transformation: Lactic acid can transform tumor-infiltrating macrophages from cancer-fighting to cancer-promoting types.

  • Immune Suppression Enhancement: It enhances the immunosuppressive functions of regulatory T cells and can even turn PD-1 inhibitors into agents that promote immune suppression.

 

A study published on July 4th in the prestigious journal Nature by a joint team from the UK’s Cancer Research Institute and Sun Yat-sen University in China has revealed another surprising role of lactic acid.

This study demonstrates that tumors can use lactic acid to shield themselves from the damage caused by radiotherapy and chemotherapy by promoting the repair of DNA breaks, thereby maintaining genomic stability in cancer cells.

 

Lactic Acid: The Unexpected Ally of Cancer Cells in DNA Repair and Chemoresistance

 


Research Methodology and Findings

The researchers aimed to understand how gastric cancer copes with DNA damage from neoadjuvant chemotherapy. They analyzed post-surgical specimens from gastric cancer patients treated with platinum-based chemotherapy, using proteomics and untargeted metabolomics. They found that lactate dehydrogenase (LDHA), an enzyme responsible for lactic acid production, was highly upregulated in drug-resistant tumors. Moreover, lactic acid was the most abundant metabolite in these resistant tumors.

When chemoresistant human gastric cancer cells were transplanted into mice, lactic acid salts alone did not affect tumor growth. However, lactic acid salts weakened the tumor-suppressing effects of cisplatin and reduced the survival time of the mice. Depleting the lactic acid transporter MCT1 in tumor cells negated lactic acid’s ability to promote chemoresistance. Similarly, lactic acid also enhanced tumor resistance to radiotherapy.

Mechanism of Action

Lactic acid significantly increased the efficiency of homologous recombination (HR) repair in cancer cells but only slightly increased non-homologous end joining (NHEJ) repair efficiency. This indicates that lactic acid helps maintain genomic stability in cancer cells through HR-mediated DNA repair, aiding in their survival.

The researchers explored the specific molecular mechanisms behind this process and found that lactylation played a crucial role. They identified that lactylation of the DNA repair protein NBS1, a key component of the MRN complex (MRE11-RAD50-NBS1), was pivotal. When NBS1’s lysine at position 388 (K388) was lactylated, it enhanced the interaction between MRE11, RAD50, and NBS1, promoting the formation of the MRN complex and the recruitment of HR proteins to DNA break sites.

Therapeutic Implications

The team tested two LDHA inhibitors and found that stiripentol, an approved anti-epileptic drug, significantly reduced lactic acid production and NBS1 K388 lactylation. In patient-derived tumor organoids (PDO) and patient-derived xenograft (PDX) mouse models, stiripentol combined with chemotherapy or radiotherapy showed strong synergistic anticancer effects and extended the survival of the mice.

Clinical Relevance

Further analysis revealed that high levels of LDHA expression and NBS1 K388 lactylation were associated with clinical resistance to neoadjuvant chemotherapy and poorer overall survival in cancer patients. This study confirms the critical role of lactylation in tumor survival and suggests that targeting lactylation could enhance the efficacy of radiotherapy and chemotherapy, with stiripentol showing potential as a synergistic agent.

This groundbreaking research not only expands our understanding of lactic acid’s role in cancer but also offers promising new avenues for improving cancer treatment outcomes.

Lactic Acid: The Unexpected Ally of Cancer Cells in DNA Repair and Chemoresistance


References:

[1].Zong et al., Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell. 2024. doi:10.1016/j.cell.2024.04.002

[2].Bohn T, Rapp S, Luther N, et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol. 2018;19(12):1319-1329. doi:10.1038/s41590-018-0226-8

[3].Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575-580. doi:10.1038/s41586-019-1678-1

[4].Qian Y, Galan-Cobo A, Guijarro I, et al. MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. Cancer Cell. 2023;41(7):1363-1380.e7. doi:10.1016/j.ccell.2023.05.015

[5].Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021;591(7851):645-651. doi:10.1038/s41586-020-03045-2

[6].Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40(2):201-218.e9. doi:10.1016/j.ccell.2022.01.001

[7].Chen, H., Li, Y., Li, H. et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024. doi:10.1038/s41586-024-07620-9

[8].https://www.chictr.org.cn/showproj.html?proj=221035

(source:internet, reference only)

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