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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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References

  1. Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90. https://doi.org/10.3322/caac.20107

    Article  PubMed  Google Scholar 

  2. Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yi J, Minikes AM, Jiang X (2019) Aiming at cancer in vivo: ferroptosis-inducer delivered by nanoparticles. Cell Chem Biol 26:621–622. https://doi.org/10.1016/j.chembiol.2019.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kim SE, Zhang L, Ma K et al (2016) Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol 11:977–985. https://doi.org/10.1038/nnano.2016.164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gai C, Yu M, Li Z et al (2020) Acetaminophen sensitizing erastin-induced ferroptosis via modulation of Nrf2/heme oxygenase-1 signaling pathway in non-small-cell lung cancer. J Cell Physiol 235:3329–3339. https://doi.org/10.1002/jcp.29221

    Article  CAS  PubMed  Google Scholar 

  6. Stockwell BR, Friedmann Angeli JP, Bayir H et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171:273–285. https://doi.org/10.1016/j.cell.2017.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jiang Y, Bao H, Ge Y et al (2015) Therapeutic targeting of GSK3beta enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C. Gut 64:168–179. https://doi.org/10.1136/gutjnl-2013-306043

    Article  CAS  PubMed  Google Scholar 

  8. Phyu SM, Tseng CC, Smith TAD (2019) CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor. MAGMA 32:227–235. https://doi.org/10.1007/s10334-018-0719-3

    Article  CAS  PubMed  Google Scholar 

  9. Zhang A, Lakshmanan J, Motameni A et al (2018) MicroRNA-203 suppresses proliferation in liver cancer associated with PIK3CA, p38 MAPK, c-Jun, and GSK3 signaling. Mol Cell Biochem 441:89–98. https://doi.org/10.1007/s11010-017-3176-9

    Article  CAS  PubMed  Google Scholar 

  10. Chang LC, Chiang SK, Chen SE et al (2018) Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis. Cancer Lett 416:124–137. https://doi.org/10.1016/j.canlet.2017.12.025

    Article  CAS  PubMed  Google Scholar 

  11. Song MK, Lee JH, Ryoo IG et al (2019) Bardoxolone ameliorates TGF-beta1-associated renal fibrosis through Nrf2/Smad7 elevation. Free Radic Biol Med 138:33–42. https://doi.org/10.1016/j.freeradbiomed.2019.04.033

    Article  CAS  PubMed  Google Scholar 

  12. Conrad M, Angeli JP, Vandenabeele P et al (2016) Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 15:348–366. https://doi.org/10.1038/nrd.2015.6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang WS, SriRamaratnam R, Welsch ME et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331. https://doi.org/10.1016/j.cell.2013.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ni Chonghaile T, Sarosiek KA, Vo TT et al (2011) Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334:1129–1133. https://doi.org/10.1126/science.1206727

    Article  CAS  PubMed  Google Scholar 

  15. Bebber CM, Muller F, Prieto Clemente L et al (2020) Ferroptosis in cancer cell biology. Cancers (Basel). https://doi.org/10.3390/cancers12010164

    Article  Google Scholar 

  16. Shan X, Li S, Sun B et al (2020) Ferroptosis-driven nanotherapeutics for cancer treatment. J Control Release 319:322–332. https://doi.org/10.1016/j.jconrel.2020.01.008

    Article  CAS  PubMed  Google Scholar 

  17. Guan Q, Guo R, Huang S et al (2020) Mesoporous polydopamine carrying sorafenib and SPIO nanoparticles for MRI-guided ferroptosis cancer therapy. J Control Release 320:392–403. https://doi.org/10.1016/j.jconrel.2020.01.048

    Article  CAS  PubMed  Google Scholar 

  18. Theeuwes WF, Gosker HR, Langen RCJ et al (2017) Inactivation of glycogen synthase kinase-3beta (GSK-3beta) enhances skeletal muscle oxidative metabolism. Biochim Biophys Acta 1863:3075–3086. https://doi.org/10.1016/j.bbadis.2017.09.018

    Article  CAS  Google Scholar 

  19. Ranea-Robles P, Launay N, Ruiz M et al (2018) Aberrant regulation of the GSK-3beta/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. EMBO Mol Med. https://doi.org/10.15252/emmm.201708604

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yu J, Liu D, Sun X et al (2019) CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/beta-catenin signaling via transactivation of GSK-3beta and Axin2 expression. Cell Death Dis 10:26. https://doi.org/10.1038/s41419-018-1263-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arioka M, Takahashi-Yanaga F, Kubo M et al (2017) Anti-tumor effects of differentiation-inducing factor-1 in malignant melanoma: GSK-3-mediated inhibition of cell proliferation and GSK-3-independent suppression of cell migration and invasion. Biochem Pharmacol 138:31–48. https://doi.org/10.1016/j.bcp.2017.05.004

    Article  CAS  PubMed  Google Scholar 

  22. Aristizabal-Pachon AF, Castillo WO (2017) Role of GSK3beta in breast cancer susceptibility. Cancer Biomark 18:169–175. https://doi.org/10.3233/cbm-160120

    Article  CAS  PubMed  Google Scholar 

  23. Zhu Q, Yang J, Han S et al (2011) Suppression of glycogen synthase kinase 3 activity reduces tumor growth of prostate cancer in vivo. Prostate 71:835–845. https://doi.org/10.1002/pros.21300

    Article  CAS  PubMed  Google Scholar 

  24. Shintoku R, Takigawa Y, Yamada K et al (2017) Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci 108:2187–2194. https://doi.org/10.1111/cas.13380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cuadrado A, Kugler S, Lastres-Becker I (2018) Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biol 14:522–534. https://doi.org/10.1016/j.redox.2017.10.010

    Article  CAS  PubMed  Google Scholar 

  26. Fan Z, Wirth AK, Chen D et al (2017) Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis 6:e371. https://doi.org/10.1038/oncsis.2017.65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Roh JL, Kim EH, Jang H et al (2017) Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 11:254–262. https://doi.org/10.1016/j.redox.2016.12.010

    Article  CAS  PubMed  Google Scholar 

  28. Armagan G, Sevgili E, Gurkan FT et al (2019) Regulation of the Nrf2 pathway by glycogen synthase kinase-3beta in MPP(+)-induced cell damage. Molecules 24:1377. https://doi.org/10.3390/molecules24071377

    Article  CAS  PubMed Central  Google Scholar 

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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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  8. Wentong Li
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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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