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IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells

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Abstract

Purpose

Breast cancer is the most commonly diagnosed cancer in women, and triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of all breast cancers. TNBC is highly invasive and malignant. Due to the lack of relevant receptor markers, the prognosis of TNBC is poor and the five-year survival rate is low. Paclitaxel is the first-line drug for the treatment of TNBC, which can inhibit cell mitosis. However, many patients develop drug resistance during treatment, leading to chemotherapy failure. Therefore, finding new therapeutic combinations to overcome TNBC drug resistance can provide new strategies for improving the survival rate of TNBC patients.

Methods

Cell viability assay, RT-qPCR, Colony formation assay, Western blot, and Xenogeneic transplantation methods were used to investigate roles and mechanisms of IRE1α/XBP1s pathway in the paclitaxel-resistant TNBC cells, and combined paclitaxel and IRE1α inhibitor in the treatment of TNBC was examined in vitro and in vivo.

Results

We found activation of UPR in paclitaxel-resistant cells, confirming that IRE1α/XBP1 promotes paclitaxel resistance in TNBC. In addition, we demonstrated that the combination of paclitaxel and IRE1α inhibitors can synergistically inhibit the proliferation of TNBC tumors both in vitro and in vivo,suggesting that IRE1α inhibitors combined with paclitaxel may be a new treatment option for TNBC.

Conclusions

In this study, we demonstrated the important role of IRE1α signaling in mediating paclitaxel resistance and identified that combination therapies targeting IRE1α signaling could overcome paclitaxel resistance and enhance chemotherapy efficacy.

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Data availability

All data yield or analyzed during this study included in this article.

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Acknowledgements

This work was supported by the grants from National Natural Science Foundation of China (82073310, 82373146), ECNU Construction Fund of Innovation and Entrepreneurship Laboratory (44400-20201-532300/021). We thank the Instruments Sharing Platform of School of LifeSciences, East China Normal University.

Author information

Author notes

  1. Min Wu, Lin Zhang and Lifu Pi have contributed equally to this work.

Authors and Affiliations

  1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dong Chuan Rd, Shanghai, 200241, China

    Min Wu, Lin Zhang, Layang Liu, Siyu Wang, Yujie Wu, Hongli Pan, Mingyao Liu & Zhengfang Yi

  2. Shanghai World Foreign Language Academy, Shanghai, 200030, China

    Lifu Pi

  3. Department of Reproductive Medicine, Affiliated Hospital of **ing Medical University, **ing Medical University, **ing, Shandong, 272000, China

    Hongli Pan

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  1. Min Wu
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Contributions

M.W., L.Z., and L.P. designed the experiments. M.W., L.Z., L.P., L.L., S.W. and H.P. performed the experiments. M.W., L.Z., L.P., L.L., S.W., H.P. and Z.Y. performed the data analysis. M.W., M.L. and Z.Y. wrote the manuscript.

Corresponding author

Correspondence to Zhengfang Yi.

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Animal ethical

All animals mentioned in this article were purchased from the Animal Center of East China Normal University. Animal care and maintenance complied with the guidelines of the Animal Investigation Committee of the Institute of Biomedical Sciences, East China Normal University.

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The authors declare that they have no competing interests.

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Wu, M., Zhang, L., Pi, L. et al. IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00961-7

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