Departamento de Biofísica e Biometria, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, 20551-030, Brazil.
Laboratório de Alimentos Funcionais, Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
Cell Biochem Biophys. 2024 Dec;82(4):3507-3516. doi: 10.1007/s12013-024-01439-x. Epub 2024 Jul 20.
Unbalanced redox status and constitutive STAT3 activation are related to several aspects of tumor biology and poor prognosis, including metastasis and drug resistance. The triple-negative breast cancer (TNBC) is listed as the most aggressive and exhibits the worst prognosis among the breast cancer subtypes. Although the mechanism of reactive oxygen species (ROS) generation led to STAT3 activation is described, there is no data concerning the STAT3 influence on redox homeostasis in TNBC. To address the role of STAT3 signaling in redox balance, we inhibited STAT3 in TNBC cells and investigated its impact on total ROS levels, contents of hydroperoxides, nitric oxide (NO), and total glutathione (GSH), as well as the expression levels of 3-nitrotyrosine (3NT), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and nuclear factor kappa B (NF-κB)/p65. Our results indicate that ROS levels depend on the STAT3 activation, while the hydroperoxide level remained unchanged, and NO and 3NT expression increased. Furthermore, GSH levels, Nrf2, and NF-κB/p65 protein levels are decreased in the STAT3-inhibited cells. Accordingly, TNBC patients' data from TCGA demonstrated that both STAT3 mRNA levels and STAT3 signature are correlated to NF-κB/p65 and Nrf2 signatures. Our findings implicate STAT3 in controlling redox balance and regulating redox-related genes' expression in triple-negative breast cancer.
不平衡的氧化还原状态和组成性 STAT3 激活与肿瘤生物学的几个方面和不良预后相关，包括转移和耐药性。三阴性乳腺癌 (TNBC) 被列为最具侵袭性的乳腺癌亚型，预后最差。尽管已经描述了活性氧 (ROS) 生成导致 STAT3 激活的机制，但关于 STAT3 对 TNBC 中氧化还原平衡的影响尚无数据。为了研究 STAT3 信号在氧化还原平衡中的作用，我们在 TNBC 细胞中抑制了 STAT3，并研究了其对总 ROS 水平、过氧化物含量、一氧化氮 (NO) 和总谷胱甘肽 (GSH) 以及 3-硝基酪氨酸 (3NT)、核因子 (erythroid-derived 2)-样 2 (Nrf2) 和核因子 kappa B (NF-κB)/p65 的表达水平的影响。我们的结果表明，ROS 水平取决于 STAT3 的激活，而过氧化物水平保持不变，NO 和 3NT 的表达增加。此外，STAT3 抑制细胞中的 GSH 水平、Nrf2 和 NF-κB/p65 蛋白水平降低。相应地，TCGA 中 TNBC 患者的数据表明，STAT3 mRNA 水平和 STAT3 特征与 NF-κB/p65 和 Nrf2 特征相关。我们的发现表明 STAT3 参与控制三阴性乳腺癌中的氧化还原平衡，并调节与氧化还原相关的基因表达。
