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Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma

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Abstract

Objective

Metabolic disorders are regarded as hallmarks of multiple myeloma (MM) and are responsible for rapid cancer cell proliferation and tumor growth. However, the exact biological roles of metabolites in MM cells have not been fully explored. This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid (Lac) in the proliferation of myeloma cells and cell sensitivity to bortezomib (BTZ).

Methods

Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients. The CCK8 assay and flow cytometry were used to detect cell proliferation, apoptosis, and cell cycle changes. Western blotting was used to detect the potential mechanism and apoptosis- and cycle-related protein changes.

Results

Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients. It was significantly correlated with Durie-Salmon Staging (DS Staging) and the International Staging System (ISS Staging) and the serum and urinary involved/uninvolved free light chain ratios. Patients with relatively high lactate levels had a poor treatment response. Moreover, in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells, which was accompanied by an increased proportion of S-phase cells. In addition, Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2 (NFkB2) and RelB.

Conclusion

Metabolic changes are important in MM cell proliferation and treatment response; lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China

    Na-ya Ma, Qiong Li, Xin-lei Li, Yun-jing Zeng, De-zhi Huang, Yi-shuo Duan, Jing Xia, Bang-dong Liu, Ling-yi Rao, Jun Rao & Xi Zhang

  2. State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037, China

    Na-ya Ma, Qiong Li, Xin-lei Li, Yun-jing Zeng, De-zhi Huang, Yi-shuo Duan, Jing Xia, Bang-dong Liu, Ling-yi Rao, Jun Rao & Xi Zhang

  3. National Clinical Research Center for Hematologic Diseases, First Affiliated Hospital of Soochow University, Soochow, 215031, China

    Jun Rao & Xi Zhang

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  1. Na-ya Ma
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  2. Qiong Li
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Corresponding authors

Correspondence to Jun Rao or Xi Zhang.

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The authors declare that they have no conflict of interests.

Additional information

This work was supported by grants from the National Natural Science Foundation of China (No. 82070208), the Military Clinical Medical Innovation Project of Xinqiao Hospital (No. 2021JSLC0003), the National Natural Science Foundation of Chongqing (No. cstc2020jcyj-msxmX0433), the Translational Research Grant of NCRCH (Nos. 2020ZKZC02, 2021WWB05), and the Chongqing Science and Health Joint Medical Research Project (Nos. 2021MSXM226, 2023QNXM047).

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Ma, Ny., Li, Q., Li, Xl. et al. Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma. CURR MED SCI 43, 679–688 (2023). https://doi.org/10.1007/s11596-023-2747-0

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  • DOI: https://doi.org/10.1007/s11596-023-2747-0

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