The Influence of AQP5 on the Response to Hydrogen Peroxide in Breast Cancer Cell Lines
Ivan Lučić1, Monika Mlinarić1, Ana Čipak Gašparović1
1Laboratory for Membrane Transport and Signaling, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička Cesta 54, 10000 Zagreb, Croatia.
Abstract:
Breast cancer is a heterogeneous disease with varying responses to therapies. While targeted treatments have advanced, conventional therapies inducing oxidative stress remain widely used. H2O2 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 H2O2 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. H2O2 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 AQP3 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.
Insights
Aquaporin-5 (AQP5) affects breast cancer cell response to hydrogen peroxide (H2O2) therapy. Overexpressing AQP5 altered cell viability and oxidative stress markers, indicating a cell-type-specific role in therapy resistance.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Breast cancer treatment often involves therapies that induce oxidative stress.
- Hydrogen peroxide (H2O2) is a key molecule in cellular signaling and function.
- Aquaporins, specifically AQP5, regulate H2O2 transport and are implicated in poor prognosis and therapy resistance.
Purpose of the Study:
- To investigate the role of Aquaporin-5 (AQP5) in the acute oxidative stress response of breast cancer cells.
- To determine how AQP5 overexpression influences cell viability, reactive oxygen species (ROS) levels, and associated signaling pathways under H2O2 treatment.
Main Methods:
- AQP5 was overexpressed in MCF7 (HR+), SkBr-3 (HER2+), and SUM 159 (TNBC) breast cancer cell lines.
- Cells were exposed to hydrogen peroxide (H2O2) for 24 hours.
- Assessed were cell viability, intracellular ROS, AQP3/AQP5 expression, and key signaling pathways (NRF2, PI3K/AKT, FOXOs).
Main Results:
- AQP5 overexpression led to cell-type-specific responses to H2O2.
- Viability decreased in SkBr-3-AQP5 and MCF7-AQP5 cells; ROS increased in MCF7-AQP5 but decreased in SUM 159-AQP5 cells.
- Differential modulation of NRF2, FOXOs, and PI3K/AKT pathways was observed, including NRF2/AKR1B10 activation in MCF7-AQP5 and reduced FOXO1 in SUM 159-AQP5.
Conclusions:
- AQP5 plays a significant, cell-type-specific role in the oxidative stress response of breast cancer cells.
- The findings suggest AQP5 influences breast cancer cell behavior and response to H2O2-based therapies.
- Further research is warranted to elucidate AQP5's precise mechanisms in breast cancer therapy resistance.
