Article | Published:

Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide

Oncogene (2018) | Download Citation

Abstract

Radiotherapy significantly improves the therapeutic outcomes and survival of breast cancer patients. However, the acquired resistance to this therapeutic modality is a major clinical challenge. Here we show that ionizing irradiation (IR)-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) at the Tyr705 residue and the induction of reactive oxygen species (ROS) in wild-type and radioresistant MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines. Comparing with radiosensitive parental TNBC cells, significantly low levels of ROS and higher protein levels of phospho-STAT3 and Bcl-2 were observed in TNBC cells with acquired radioresistance. Moreover, knockdown of STAT3 by shRNA sensitized the TNBC cells to IR. Niclosamide, a potent inhibitor of STAT3, overcame the radioresistance in TNBC cells via inhibition of STAT3 and Bcl-2 and induction of ROS. In combination with radiation, niclosamide treatment resulted in significant increase of ROS generation and induction of apoptosis in parental and radioresistant TNBC cells in vitro and TNBC xenograft tumors in vivo. These findings demonstrate that activation of STAT3 and Bcl-2 and reduction of ROS contribute to the development of radioresistance in TNBC, and niclosamide acts as a potent radiosensitizer via inhibiting STAT3 and Bcl-2 and increasing ROS generation in TNBC cells and xenograft tumors. Our findings suggest that niclosamide in combination with irradiation may offer an effective alternative approach for restoring the sensitivity of radioresistant TNBC cells to IR for improved therapeutic efficacy and outcomes.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81472495, 81572969, 81172127, 81703169, and 81730086); the Technology and Development and Research Projects for Research Institutes, Chinese Ministry of Science and Technology (2014EG150134); the Tianjin Science and Technology Support Plan Project (14ZCZDSY00001); the CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2016-I2M-1-017); in part by startup funds from The University of Texas M.D. Anderson Cancer Center (to QS); Prevent Cancer Foundation Holden Family Research Grant in Breast Cancer Prevention (to QS); and Seed Funding Research Program of Duncan Family Institute (to QS). We also thank Amy Ninetto, PhD, ELS, Department of Scientific Publications, The University of Texas MD Anderson Cancer Center, for her editing of the manuscript.

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Affiliations

  1. Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, 300192, China

    • Lu Lu
    • , Jiali Dong
    •  & Saijun Fan
  2. Department of Radiation Oncology, First Affiliated Hospital, Soochow University, Suzhou, Jiangshu, 215006, China

    • Lili Wang
  3. Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    • Lili Wang
    • , Qing Xia
    • , Dan Zhang
    • , Hyejin Kim
    • , Tao Yin
    •  & Qiang Shen
  4. Department of Oncology, Affiliated Renji Hospital, Shanghai Jiaotong University School of Medicine, Pancreatic Cancer Center of Shanghai Jiaotong University, Shanghai, 200127, China

    • Qing Xia
  5. College of Basic Medical Science, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, China

    • Dan Zhang
  6. Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    • Tao Yin

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The authors declare that they have no conflict of interest.

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Correspondence to Saijun Fan or Qiang Shen.

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https://doi.org/10.1038/s41388-018-0340-y

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