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Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway

Cancer Gene Therapy volume 30, pages 647–658 (2023)Cite this article

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A Correction to this article was published on 15 November 2022

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Abstract

Chemotherapy can improve the prognosis and overall survival of breast cancer patients, but chemoresistance continues a major problem in clinical. Most breast cancer is estrogen receptor (ER) positive but responds less to neoadjuvant or adjuvant chemotherapy than ER-negative breast cancer. The Nogo-B receptor (NgBR) increases the chemoresistance of ER-positive breast cancer by facilitating oncogene signaling pathways. Here, we further investigated the potential role of NgBR as a novel target to overcome glycolysis-dependent paclitaxel resistance in ER-positive breast cancer. NgBR knockdown inhibited glycolysis and promoted paclitaxel-induced apoptosis by attenuating HIF-1α expression in ER-positive breast cancer cells via NgBR-mediated estrogen receptor alpha (ERα)/hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-kappa B subunit (NF-κB)/HIF-1α signaling pathways. A ChIP assay further confirmed that NgBR overexpression not only facilitates ERα binding to HIF-1α and GLUT1 genes but also promotes HIF-1α binding to GLUT1, HK2, and LDHA genes, which further promotes glycolysis and induces paclitaxel resistance. In conclusion, our study suggests that NgBR expression is essential for maintaining the metabolism and paclitaxel resistance of ER-positive breast cancer, and the NgBR can be a new therapeutic target for improving chemoresistance in ER-positive breast cancer.

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Fig. 1: NgBR and glycolysis-related protein expressions were upregulated in MCF-7/PTX cells.
Fig. 2: NgBR knockdown promoted apoptosis by inhibiting glycolysis in MCF-7/PTX cells.
Fig. 3: E2 treatment and NgBR overexpression promoted glycolysis via the expression of HIF-1α.
Fig. 4: NgBR regulated HIF-1α expression via phosphorylation of NF-κB p65.
Fig. 5: NgBR modulated ERα binding to the promoter region of HIF-1α and GLUT1 genes.
Fig. 6: NgBR modulated HIF-1α binding to the promoter region of GLUT1, HK2, and LDHA genes.

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Acknowledgements

Thanks to the following projects for supporting this study: National Natural Science Foundation of China (No. 82003173), Jilin Province Department of Finance (JLSCZD2019-030), Health Commission of Jilin Province (No. 2020Q016).

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Author notes

  1. These authors contributed equally: Qing Robert Miao, Ying Jin, Zhimin Fan.

Authors and Affiliations

  1. Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China

    Chang Liu, Sijie Li, Xiaoxiao Zhang, Liying Li, Ying Jin & Zhimin Fan

  2. Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

    Chang Liu

  3. Institute Department of Ultrasonography, China-Japan Union Hospital of Jilin University, Changchun, China

    Chunxiang Jin

  4. CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R & A Center, Dalian Institute, Liaoning, China

    Baofeng Zhao

  5. Department of Foundations of Medicine, NYU Long Island School of Medicine, New York, NY, USA

    Qing Robert Miao

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Contributions

CL: conceptualization, data curation, formal analysis, investigation, writing—original draft and writing—review & editing; SL: supervision and methodology; XZ: data curation and validation; CJ: resources and supervision; BZ: resources and supervision; LL: methodology and validation; QRM: conceptualization, supervision, and writing—review and editing; YJ: conceptualization, funding acquisition, resources, supervision and writing—review and editing; ZF: conceptualization, funding acquisition, resources, and writing—review & editing.

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Correspondence to Qing Robert Miao, Ying Jin or Zhimin Fan.

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All patients signed informed consent for this study, and their samples were anonymous. The research has been allowed by the Ethics Committee of the First Hospital of Jilin University (2020-066).

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Liu, C., Li, S., Zhang, X. et al. Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway. Cancer Gene Ther 30, 647–658 (2023). https://doi.org/10.1038/s41417-022-00542-6

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