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Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer

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Abstract

Ferroptosis is a newly discovered form of regulated cell death and characterized by an iron-dependent accumulation of lethal lipid reactive oxygen species (ROS), ferroptosis may exhibit a novel spectrum of clinical activity for cancer therapy. However, the significance of ferroptosis in the context of carcinoma biology is still emerging. Glycogen synthase kinase-3β (GSK-3β) has been found to be a fundamental element in weaking antioxidant cell defense by adjusting the nuclear factor erythroid 2-related factor 2 (Nrf2). In our study, decreased expression of GSK-3β was observed in the cancer tissues of breast cancer patients, results of immunohistochemistry indicated that Nrf2 was highly expressed in low-GSK-3β-expressed breast cancer tissues. The contributions of aberrant expression of GSK-3β and Nrf2 to the erastin-induced ferroptosis in breast cancer were further assessed, silence of GSK-3β blocked erastin-induced ferroptosis with less production of ROS and malondialdehyde (MDA) via upregulation of GPX4 and downregulation of arachidonate 15-lipoxygenase (Alox15), overexpression of GSK-3β enhanced erastin-triggered ferroptosis with elevated ROS and MDA. Enhanced erastin-induced ferroptosis by overexpression of GSK-3β was blocked by activating Nrf2. We further confirmed that overexpression of GSK-3β strengthened erastin-induced tumor growth inhibition in breast cancer xenograft models in vivo. In summary, our findings conclude that modulation the balance between GSK-3β/Nrf2 is a promising therapeutic approach and probably will be important targets to enhance the effect of erastin-induced ferroptosis in breast cancer.

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Funding

This work was supported by a grant from the National Natural Science Foundation of China (81572578) and The Natural Science Foundation of Shandong Province (ZR2015HL064).

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Authors and Affiliations

  1. Department of Pathology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong Province, China

    Xinghan Wu, Zihaoran Li, Chengcheng Gai & Wentong Li

  2. The Second Department of Health Care, Weifang People’s Hospital, Weifang, 261041, Shandong Province, China

    Chuanliang Liu

  3. Department of Pharmacology, Weifang Medical University, Weifang, 261053, Shandong Province, China

    Dejun Ding

  4. Department of Pathology, Shouguang People’s Hospital, Shouguang, 261053, Shandong Province, China

    Weijuan Chen

  5. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China

    Fengyun Hao

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  1. Xinghan Wu
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Contributions

WL conceived and designed the experiments. XW, ZL, CG, DD and WC performed the experiments. FH analyzed the data. XW and ZL wrote the draft; WL checked and revised the draft. All authors approved to submit this version to this publication.

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Correspondence to Wentong Li.

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Wu, X., Liu, C., Li, Z. et al. Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. Mol Cell Biochem 473, 217–228 (2020). https://doi.org/10.1007/s11010-020-03821-8

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  • DOI: https://doi.org/10.1007/s11010-020-03821-8

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