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Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer.
Mol Cell Biochem. 2020 Oct; 473(1-2):217-228.MC

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.

Authors+Show Affiliations

Department of Pathology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong Province, China.The Second Department of Health Care, Weifang People's Hospital, Weifang, 261041, Shandong Province, China.Department of Pathology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong Province, China.Department of Pathology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong Province, China.Department of Pharmacology, Weifang Medical University, Weifang, 261053, Shandong Province, China.Department of Pathology, Shouguang People's Hospital, Shouguang, 261053, Shandong Province, China.Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.Department of Pathology, Weifang Medical University, 7166# Baotong West Street, Weifang, 261053, Shandong Province, China. liwentong11@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32642794

Citation

Wu, Xinghan, et al. "Regulation of GSK3β/Nrf2 Signaling Pathway Modulated Erastin-induced Ferroptosis in Breast Cancer." Molecular and Cellular Biochemistry, vol. 473, no. 1-2, 2020, pp. 217-228.
Wu X, Liu C, Li Z, et al. Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. Mol Cell Biochem. 2020;473(1-2):217-228.
Wu, X., Liu, C., Li, Z., Gai, C., Ding, D., Chen, W., Hao, F., & Li, W. (2020). Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. Molecular and Cellular Biochemistry, 473(1-2), 217-228. https://doi.org/10.1007/s11010-020-03821-8
Wu X, et al. Regulation of GSK3β/Nrf2 Signaling Pathway Modulated Erastin-induced Ferroptosis in Breast Cancer. Mol Cell Biochem. 2020;473(1-2):217-228. PubMed PMID: 32642794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. AU - Wu,Xinghan, AU - Liu,Chuanliang, AU - Li,Zihaoran, AU - Gai,Chengcheng, AU - Ding,Dejun, AU - Chen,Weijuan, AU - Hao,Fengyun, AU - Li,Wentong, Y1 - 2020/07/08/ PY - 2020/04/21/received PY - 2020/06/27/accepted PY - 2020/7/10/pubmed PY - 2020/7/10/medline PY - 2020/7/10/entrez KW - Breast cancer KW - Ferroptosis KW - GSK-3β KW - Nrf2 KW - ROS SP - 217 EP - 228 JF - Molecular and cellular biochemistry JO - Mol. Cell. Biochem. VL - 473 IS - 1-2 N2 - 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. SN - 1573-4919 UR - https://www.unboundmedicine.com/medline/citation/32642794/Regulation_of_GSK3β/Nrf2_signaling_pathway_modulated_erastin_induced_ferroptosis_in_breast_cancer_ L2 - https://doi.org/10.1007/s11010-020-03821-8 DB - PRIME DP - Unbound Medicine ER -
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