Cytochrome b561 regulates iron metabolism by activating the Akt/mTOR pathway to promote Breast Cancer Cells proliferation.

Xiaofeng Zhou, Xinjian Guo, Jingqi Han, Miaozhou Wang, Zhen Liu, Dengfeng Ren, Jiuda Zhao, Zhanquan Li

Experimental cell research 2023 Oct 01

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Breast cancer (BC) is the leading cause of cancer-related mortality in women, necessitating the development of novel therapeutic targets. While cytochrome b561 (CYB561) expression is associated with poor prognosis in BC, the precise role of CYB561 in BC and its potential mechanisms remain unclear. In the present study, we found that CYB561 plays an essential role in BC growth. CYB561 expression was up-regulated in surgically resected cancerous tissues and in six BC cell lines. Lentivirus-mediated CYB561 knockdown in BC cells significantly reduced their proliferation, migration, and invasiveness. CYB561 participates in the regulation of iron metabolism in BC. CYB561 knockdown reduced total iron content, increased ferrous iron content, and down-regulated the expression of proteins associated with iron metabolism (transferrin receptor 1, divalent metal transporter 1, and ferritin heavy chain 1). Conversely, up-regulation of CYB561 through co-incubation with exogenous iron (ferric ammonium citrate) produced contrary outcomes. Additionally, CYB561 activated the protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling pathway in BC cells. Down-regulation of CYB561 expression inhibited the Akt/mTOR signaling pathway activity. The application of an mTOR agonist (MHY1485) rescued this negative effect, as well as the inhibitory effect of CYB561 knockdown on cell proliferation. Importantly, the dual mTOR inhibitor MLN0128 (50 nM, 48 h) down-regulated CYB561 expression and the iron metabolism-related proteins transferrin receptor, divalent metal transporter 1, and ferritin heavy chain 1, whereas the mTOR agonist MHY1485 rescued the down-regulation of CYB561 knockdown on iron metabolism-related proteins. We conclude that CYB561 promotes the proliferation of BC cells by regulating iron metabolism through the activation of the Akt/mTOR signaling pathway. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Xiaofeng Zhou, Xinjian Guo, Jingqi Han, Miaozhou Wang, Zhen Liu, Dengfeng Ren, Jiuda Zhao, Zhanquan Li. Cytochrome b561 regulates iron metabolism by activating the Akt/mTOR pathway to promote Breast Cancer Cells proliferation. Experimental cell research. 2023 Oct 01;431(1):113760