Aquaporin-3 Controls Breast Cancer Cell Migration by Regulating Hydrogen Peroxide Transport and Its Downstream Cell Signaling

Abstract

Most breast cancer mortality is due to clinical relapse associated with metastasis. CXCL12/CXCR4-dependent cell migration is a critical process in breast cancer progression; however, its underlying mechanism remains to be elucidated. Here, we show that the water/glycerol channel protein aquaporin-3 (AQP3) is required for CXCL12/CXCR4-dependent breast cancer cell migration through a mechanism involving its hydrogen peroxide (H 2 O 2 ) transport function. Extracellular H 2 O 2 , produced by CXCL12-activated membrane NADPH oxidase 2 (Nox2), was transported into breast cancer cells via AQP3. Transient H 2 O 2 accumulation was observed around the membrane during CXCL12-induced migration, which may be facilitated by the association of AQP3 with Nox2. Intracellular H 2 O 2 then oxidized PTEN and protein tyrosine phosphatase 1B (PTP1B) followed by activation of the Akt pathway. This contributed to directional cell migration. The expression level of AQP3 in breast cancer cells was related to their migration ability both in vitro and in vivo through CXCL12/CXCR4-or H 2 O 2 -dependent pathways. Coincidentally, spontaneous metastasis of orthotopic xenografts to the lung was reduced upon AQP3 knockdown. These findings underscore the importance of AQP3-transported H 2 O 2 in CXCL12/CXCR4-dependent signaling and migration in breast cancer cells and suggest that AQP3 has potential as a therapeutic target for breast cancer. Breast cancer mortality remains high owing to clinical relapse associated with metastases, primarily to the lungs, brain, and bones (1). Metastases are the result of several sequential processes, including cell migration and invasion (2). Organ-specific metastasis requires chemokine-dependent cancer cell migration toward destination sites (3). In particular, the CXCL12/CXCR4 axis is a key step in breast cancer cell migration toward the lungs (4, 5). The binding of CXCL12 to CXCR4 stimulates downstream G protein signaling, leading to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt or mitogen-activated protein kinase (MAPK) pathway. These effects regulate a variety of cellular functions, such as cell proliferation and migration, thereby contributing to cancer metastasis and progression (6). However, the underlying mechanism by which the pathways downstream of CXCL12/ CXCR4 result in breast cancer cell migration and metastasis remain to be fully elucidated.Aquaporin-3 (AQP3), a member of the aquaporin water channel family (AQP0 to -12), has the primary function of transporting water and glycerol (7,8). AQP3 is expressed in various cancer cells derived from diverse types of cancer tissues, including breast, colon, and lung (9, 10). Recent results from clinical studies have suggested the relevance of AQP3 expression in tumor progression and the prognosis of several malignant cancers (11)(12)(13)(14). In vitro studies using cancer cell lines have implicated AQP3 expression in cancer cell proliferation and migration (15-17). However, the mechanism by which AQP3 participates as a biological pore channe...

Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress

“…This barrier, however, may be overcome by the presence of some AQPs recently shown to be capable of transporting extracellular H 2 O 2 into the cells [15]. In mammalian cells, AQP3, AQP8, and AQP9 were shown to mediate H 2 O 2 membrane transport [16,17,18], which may be used for intracellular signaling in cancer cells [19]. Consequently, due to its involvement in cancer progression, we anticipated that AQP5 might also be able to facilitate H 2 O 2 permeation and have a role in cell oxidative stress response explaining, at least in part, its overexpression in cancer tissues.…”

Unveiling the Mechanisms of Aquaglyceroporin‐3 Water and Glycerol Permeation by Metadynamics

“…[8,9] AQP3 is presenti nv arious tissues, such as kidney, [8] gut [10] the respiratory tract [11] and skin. [11,13,14] Since their discovery,m any efforts have been made to characterizet he selectivity mechanisms of the different AQP subfamilies and isoforms. [11,13,14] Since their discovery,m any efforts have been made to characterizet he selectivity mechanisms of the different AQP subfamilies and isoforms.…”

“…[12] Additionally,i th as been found to be expressedi nvarious cancer types. [11,13,14] Since their discovery,m any efforts have been made to characterizet he selectivity mechanisms of the different AQP subfamilies and isoforms. Following the elucidation of the first experimental three-dimensional structures of aquaporin-1 (AQP1) [15,16] ando ft he bacterial glycerolf acilitator GlpF, [17] several valuable computational studies have contributed with important insights into the dynamics and energetics of water and glycerolc onduction in AQPs.…”

Aquaporin-3 mediates hydrogen peroxide-dependent responses to environmental stress in colonic epithelia

“…AQP3-mediated H 2 O 2 transport has been reported to modulate epidermal growth factor signaling in ECs (13) and TNF-α signaling in skin keratinocytes (14,15). In addition, AQP3-mediated H 2 O 2 transport has been shown to be important for T-cell and breast cancer cell migration (16,17), although how AQP3 contributes to these changes in cellular function remains undefined. In the colon, AQP3 is expressed in ECs, with changes in expression found in response to inflammation, and our previous studies showed that mice lacking AQP3 experienced impaired recovery after chemical-induced colitis (18,19).…”