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Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells

Oncogene volume 38, pages 5778–5791 (2019)Cite this article

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Abstract

Drug resistance is one of the major obstacles to breast cancer therapy. However, the mechanisms of how cancer cells develop chemoresistance are still not fully understood. In the present study, we found that expression of TM9SF4 proteins was much higher in adriamycin (ADM)-resistant breast cancer cells MCF-7/ADM than in its parental line wild-type breast cancer cells MCF-7/WT. shRNA-mediated knockdown of TM9SF4 preferentially reduced cell growth and triggered cell death in chemoresistant MCF-7/ADM cells compared with MCF-7/WT cells. Knockdown of TM9SF4 also reduced cell growth and triggered cell death in chemoresistant MDA-MB-231/GEM cells. Mechanistic studies showed that TM9SF4 knockdown increased protein misfolding and elevated endoplasmic reticulum (ER) stress level in MCF-7/ADM cells, as indicated by aggresome formation and upregulated expression of ER stress markers, the effect of which was reversed by a small molecule chaperone 4-phenybutyric acid. In an athymic nude mouse model of ADM-resistant human breast xenograft tumor, knockdown of TM9SF4 decreased the growth of tumor xenografts. In chemoresistant breast cancer patients, chemotherapy increased the expression of TM9SF4 proteins in breast tumor samples. Taken together, these results uncovered a novel role of TM9SF4 proteins in alleviating ER stress and protecting chemoresistant breast cancer cells from apoptotic/necrotic cell death. These results highlight a possible strategy of targeting TM9SF4 to overcome breast cancer chemoresistance.

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Acknowledgements

This work was supported by grants from Hong Kong Research Grant Committee [AoE/M-05/12, GRF/14118516, RIF/R4005-18F] and Hong Kong Innovation and Technology Fund [ITF/096/18, PiH/230/18 and PiH/049/19].

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Authors and Affiliations

  1. School of Biomedical Sciences and Li Ka Shing Institute of Health Science, the Chinese University of Hong Kong, Hong Kong, China

    Yifei Zhu, Mingxu Xie, Zhaoyue Meng, Franky Leung Chan & Xiaoqiang Yao

  2. Wuxi School of Medicine, Jiangnan University, Wuxi, China

    Yifei Zhu

  3. School of Life Science, the Chinese University of Hong Kong, Hong Kong, China

    Lai-Kwok Leung

  4. Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Xin Hu

  5. Department of Pathology, Peking University Health Science Center, Beijing, China

    Kaiwen Chi & Cuiling Liu

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  1. Yifei Zhu
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Zhu, Y., Xie, M., Meng, Z. et al. Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells. Oncogene 38, 5778–5791 (2019). https://doi.org/10.1038/s41388-019-0846-y

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