Lučić Ivan, Mlinarić Monika, Čipak Gašparović Ana, Milković Lidija
Laboratory for Membrane Transport and Signaling, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička Cesta 54, 10000 Zagreb, Croatia.
Int J Mol Sci. 2025 Mar 31;26(7):3243. doi: 10.3390/ijms26073243.
Breast cancer is a heterogeneous disease with varying responses to therapies. While targeted treatments have advanced, conventional therapies inducing oxidative stress remain widely used. HO has emerged as a therapeutic candidate due to its role in signaling and cell-function regulation. Its transport is tightly regulated through peroxiporins such as AQP5, expression of which is linked to poor prognosis and metastatic spread, and its role in therapy resistance remains underexplored. This study examined AQP5's role in the acute oxidative stress response. We overexpressed AQP5 in breast cancer cell lines with low basal levels-HR+ (MCF7), HER2+ (SkBr-3), and TNBC (SUM 159)-and exposed them to HO for 24 h. We assessed cell viability, intracellular ROS, changes in AQP3 and AQP5, and key antioxidative and cancer-related pathways (NRF2, PI3K/AKT, FOXOs). AQP5 overexpression elicited a cell-type-specific response. HO treatment reduced viability in SkBr-3-AQP5 and MCF7-AQP5 cells, increased ROS levels in MCF7-AQP5, and decreased ROS in SUM 159-AQP5. It also increased in MCF7-AQP5 and differentially affected NRF2, FOXOs, and PI3K/AKT signaling, notably activating NRF2/AKR1B10 axis in MCF7-AQP5 and decreasing FOXO1 in SUM 159-AQP5. These findings highlight the need for further research into AQP5's role in the oxidative stress response in breast cancer cells.
乳腺癌是一种对治疗反应各异的异质性疾病。尽管靶向治疗有所进展，但诱导氧化应激的传统疗法仍被广泛使用。由于其在信号传导和细胞功能调节中的作用，血红素加氧酶（HO）已成为一种治疗候选物。其转运通过水通道蛋白如AQP5受到严格调控，AQP5的表达与预后不良和转移扩散有关，而其在治疗耐药性中的作用仍未得到充分研究。本研究探讨了AQP5在急性氧化应激反应中的作用。我们在基础水平较低的乳腺癌细胞系——激素受体阳性（HR+，MCF7）、人表皮生长因子受体2阳性（HER2+，SkBr-3）和三阴性乳腺癌（TNBC，SUM 159）——中过表达AQP5，并将它们暴露于HO中24小时。我们评估了细胞活力、细胞内活性氧（ROS）、AQP3和AQP5的变化以及关键的抗氧化和癌症相关信号通路（NRF2、PI3K/AKT、FOXOs）。AQP5过表达引发了细胞类型特异性反应。HO处理降低了SkBr-3-AQP5和MCF7-AQP5细胞的活力，增加了MCF7-AQP5细胞中的ROS水平，并降低了SUM 159-AQP5细胞中的ROS水平。它还增加了MCF7-AQP5细胞中的[具体物质未明确]，并对NRF2、FOXOs和PI3K/AKT信号传导产生不同影响，特别是激活了MCF7-AQP5细胞中的NRF2/AKR1B10轴，并降低了SUM 159-AQP5细胞中的FOXO1。这些发现凸显了进一步研究AQP5在乳腺癌细胞氧化应激反应中作用的必要性。
