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Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin

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Abstract

Aberrant activation of eIF4E signalling pathway is common in breast cancer and holds potential therapeutic options. In our work, galeterone as a chemical compound under clinical trials for the treatment of prostate cancer, was identified to be effective in targeting breast cancer cells via suppressing MNK-eIF4E and β-catenin. In despite of varying IC50, galeterone at nanomolar concentrations significantly decreased viability, proliferation and migration of a panel of breast cancer cell lines regardless of clinical subtypes and genetic mutations, and to a higher extent than in normal breast cells. Galeterone significantly enhanced the effects of chemotherapeutic drugs in reducing proliferation and viability but not migration. The in vivo efficacy of galeterone as single drug alone and its ability in augmenting chemotherapy’s efficacy were also shown in breast cancer xenograft mouse model. Mechanism analysis demonstrated that galeterone decreased MNK1/2 level and phosphorylation of eIF4E. In addition, galeterone decreased β-catenin level via promoting GSK-3β-mediated β-catenin degradation, and furthermore that Akt but not CK1 was involved in β-catenin degradation by galeterone. Rescue studies demonstrated that both MNK/eIF4E and β-catenin were responsible for anti-breast cancer activity of galeterone. Our study provides pre-clinical evidence to initialize clinical trials for breast cancer using galeterone in combination with chemotherapy.

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Acknowledgements

This work was supported by Teaching Reform Research Project of Medical Department of Wuhan University (Grant No. 2019037); the Guide Foundation of Renmin Hospital of Wuhan University (Grant No. RMYD2018M78); Fundamental Research Funds for the Central Universities of China (Grant No. 2042019kf0102) and National Natural Science Foundation of China (Grant No. 81700599).

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  1. Yulin Xu and Shichong Liao are equal contributors and co-first authors.

Authors and Affiliations

  1. Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

    Yulin Xu, Shichong Liao, Lijun Wang, Yuan Wang, Wen Wei, Yi Tu & Shan Zhu

  2. Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

    Ke Su

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  1. Yulin Xu
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Xu, Y., Liao, S., Wang, L. et al. Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin. Cancer Chemother Pharmacol 87, 85–93 (2021). https://doi.org/10.1007/s00280-020-04195-w

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