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D-mannose induces TFE3-dependent lysosomal degradation of EGFR and inhibits the progression of NSCLC

Oncogene volume 42, pages 3503–3513 (2023)Cite this article

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Abstract

In non-small cell lung cancer (NSCLC), the overexpression or abnormal activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and drug resistance. EGFR tyrosine kinase inhibitors (TKIs) are currently the first-line treatment of NSCLC. However, patients inevitably acquired EGFR TKIs resistance mutations, which led to disease progression, so it is urgent to find new treatment. Here, we report that D-mannose up-regulates lysosomal activity by enhancing TFE3-mediated lysosomal biogenesis, thereby increasing the degradation of EGFR and significantly down-regulating its protein level. Therefore, D-mannose significantly inhibited the proliferation, migration and invasion of wild-type EGFR (WT-EGFR) and EGFR mutant cells (E746-A750 deletion, L858R and T790M mutations) in vitro. Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.

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Fig. 1: Identification of D-mannose as a new regulator of EGFR expression.
Fig. 2: D-mannose significantly down-regulates EGFR protein level.
Fig. 3: Lysosomal pathway contributes to D-mannose-mediated down-regulation of EGFR.
Fig. 4: D-mannose increases the biogenesis of lysosome and promotes the degradation of EGFR via lysosome.
Fig. 5: D-mannose inhibits the proliferation, migration and invasion of NSCLC cells in vitro.
Fig. 6: D-mannose significantly inhibits the growth of xenograft tumor in vivo.

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Data availability

All data supporting the findings of this study are available from the corresponding author (Lei Lv, lvlei@fudan.edu.cn) upon request.

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Acknowledgements

We are grateful to members of LL laboratory for discussion throughout this study. This work was supported by the National Key R&D Program of China (2020YFA0803400/2020YFA0803402, 2022YFA0807100), the National Natural Science Foundation of China (82172936, 81972620, 82121004, 82372754, 82073128 and 32000918), Shanghai Natural Science Foundation (General Program, No. 20ZR1461900), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning and the Fundamental Research Funds for the Central Universities, “Cross” Research Fund Project of the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (JYJC202207).

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Authors and Affiliations

  1. Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Xue Sun, Yue Dai, Jing He, Wenjing Dong & Lei Lv

  2. Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, China

    Hongchen Li & Yanping Xu

  3. Department of Thoracic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Xuhui Yang & Mingsong Wang

  4. Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Xiao Xie

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Contributions

XS played major roles in designing and doing the experiments, analyzing the results and organizing the figures; YD, JH, HL, XY and WD helped to conduct the experiments; XX, MW, YX and LL conceived and designed the study; LL supervised the study; and XS and LL wrote the manuscript.

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Correspondence to Xiao Xie, Mingsong Wang, Yanping Xu or Lei Lv.

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Sun, X., Dai, Y., He, J. et al. D-mannose induces TFE3-dependent lysosomal degradation of EGFR and inhibits the progression of NSCLC. Oncogene 42, 3503–3513 (2023). https://doi.org/10.1038/s41388-023-02856-7

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