AQP3-Dependent PI3K/Akt Modulation in Breast Cancer Cells

Abstract

Aquaporin 3 (AQP3) is a peroxiporin, a membrane protein that channels hydrogen peroxide in addition to water and glycerol. AQP3 expression also correlates with tumor progression and malignancy and is, therefore, a potential target in breast cancer therapy. In addition, epithelial growth factor receptor (EGFR) plays an important role in breast cancer. Therefore, we investigated whether disruption of the lipid raft harboring EGFR could affect AQP3 expression, and conversely, whether AQP3 silencing would affect the EGFR/phosphoinositide-3-kinase (PI3K)/Protein kinase B (PKB or Akt) signaling pathway in breast cancer cell lines with different malignant capacities. We evaluated H2O2 uptake, cell migratory capacity, and expression of PI3K, pAkt/Akt in three breast cancer cell lines, MCF7, SkBr3, and SUM159PT, and in the nontumorigenic breast epithelial cell line MCF10A. Our results show different responses between the tested cell lines, especially when compared to the nontumorigenic cell line. Neither lipid raft disruption nor EGF stimuli had an effect on PI3K/Akt pathway in MCF10A cell line. AQP3-silencing in SkBr3 and SUM159PT showed that AQP3 can modulate PI3K/Akt activation in these cells. Interestingly, SUM159PT cells increase nuclear factor-E2–related factor 2 (NRF2) in response to lipid raft disruption and EGF stimuli, suggesting an oxidative-dependent response to these treatments. These results suggest that in breast cancer cell lines, AQP3 is not directly related to PI3K/Akt pathway but rather in a cell-line-dependent manner.

AQP3 Promotes the Invasion and Metastasis in Cervical Cancer by Regulating NOX4-derived H2O2 Activation of Syk/PI3K/Akt Signaling Axis

“…Next, we examined whether changes in AQP3 expression affected the PI3K/Akt-related signaling pathways, given previous suggestions of AQP3's role in cancer progression through this pathway 27 , 28 . As shown in Figure 3 B, the knockdown of AQP3 in HeLa cells with different concentrations of TGF-β1 reduced the levels of phosphorylated PI3K p85α and Akt, while the total protein expression level was almost unchanged.…”

“…Additionally, silencing of AQP3 reduces MMP expression in gastric cancer cells and attenuates invasion and metastasis of gastric cancer cells through a PI3K/Akt-dependent manner 27 . In breast cancer AQP3 has also been shown to regulate oxidative responses and PI3K/Akt activation, affecting its progression 28 , 36 . These studies all support our view that H 2 O 2 acts as a second messenger to promote the progression of cervical cancer through the mediation of AQP3.…”

The Involvement of Peroxiporins and Antioxidant Transcription Factors in Breast Cancer Therapy Resistance

“…FGFR/PI3K and FGFR/ERK signaling pathways play a crucial roles in FGF-2-induced AQP3 expression and contribute to cell migration and metastasis in breast cancer [43]. AQP3-mediated modulation of the PI3K/AKT signaling pathway is specific to different breast cancer cell types [44]. Downregulation of AQP3 reduces proliferation, migration and invasiveness of the MDA-MB-231 TNBC cell line, and enhances the susceptibility of these cells to 5-FU [45].…”

The Aquaporin 3 Polymorphism (rs17553719) Is Associated with Sepsis Survival and Correlated with IL-33 Secretion

“…This indicates that AQPs may represent novel biomarkers of sepsis [6,11]. However, aquaporin-3 (AQP3) could be of special interest, as it was demonstrated that AQP3 participates in the regulation of pulmonary and intestinal function as well as immune cells in sepsis [6,8,12,13]. AQP3 is a 30 kDa hydrophobic protein and is part of the aquaporin family [12].…”

“…However, aquaporin-3 (AQP3) could be of special interest, as it was demonstrated that AQP3 participates in the regulation of pulmonary and intestinal function as well as immune cells in sepsis [6,8,12,13]. AQP3 is a 30 kDa hydrophobic protein and is part of the aquaporin family [12]. AQP3 expression can be found in various parts of the intestine, regulates the proliferation and migration of intestinal epithelial cells, and is responsible for glycerol and hydrogen peroxide transport [13].…”