Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, 810001, China; Pathology Department, Affiliated Hospital of Qinghai University, Xining, 810001, China.
Pathology Department, Affiliated Hospital of Qinghai University, Xining, 810001, China.
Exp Cell Res. 2023 Oct 1;431(1):113760. doi: 10.1016/j.yexcr.2023.113760. Epub 2023 Aug 26.
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.
乳腺癌（BC）是女性癌症相关死亡的主要原因，需要开发新的治疗靶点。虽然细胞色素 b561（CYB561）的表达与 BC 的不良预后相关，但 CYB561 在 BC 中的确切作用及其潜在机制仍不清楚。在本研究中，我们发现 CYB561 在 BC 生长中发挥着重要作用。CYB561 的表达在手术切除的癌组织和六种 BC 细胞系中上调。BC 细胞中慢病毒介导的 CYB561 敲低显著降低了它们的增殖、迁移和侵袭能力。CYB561 参与了 BC 中的铁代谢调节。CYB561 敲低降低了总铁含量，增加了亚铁含量，并下调了与铁代谢相关的蛋白表达（转铁蛋白受体 1、二价金属转运蛋白 1 和铁蛋白重链 1）。相反，通过与外源性铁（柠檬酸铁铵）共孵育来上调 CYB561 则产生了相反的结果。此外，CYB561 在 BC 细胞中激活了蛋白激酶 B/哺乳动物雷帕霉素靶蛋白（Akt/mTOR）信号通路。下调 CYB561 表达抑制了 Akt/mTOR 信号通路活性。应用 mTOR 激动剂（MHY1485）挽救了这种负效应，以及 CYB561 敲低对细胞增殖的抑制作用。重要的是，双重 mTOR 抑制剂 MLN0128（50 nM，48 h）下调了 CYB561 表达和铁代谢相关蛋白转铁蛋白受体、二价金属转运蛋白 1 和铁蛋白重链 1，而 mTOR 激动剂 MHY1485 挽救了 CYB561 敲低对铁代谢相关蛋白的下调作用。我们得出结论，CYB561 通过激活 Akt/mTOR 信号通路调节铁代谢，促进 BC 细胞的增殖。
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