Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H2O2). Here, we show that H2O2, imported via AQP3, is involved in nuclear factor-κB (NF-κB) signalling in keratinocytes and in the pathogenesis of psoriasis. IL-23-mediated induction of psoriasis is reduced in AQP3 knockout mice (AQP3 −/−), and is accompanied by impaired NF-κB activation and intracellular H2O2 accumulation. In primary keratinocyte cultures, cellular import of H2O2 produced by membrane NADPH oxidase 2 (Nox2) in response to TNF-α is facilitated by AQP3 and required for NF-κB activation by regulation of protein phosphatase 2A. As AQP3 associates with Nox2, we propose that this interplay constitutes H2O2-mediated signalling in response to TNF-α stimulation. Collectively, these data indicate that AQP3-facilitated H2O2 transport is required for NF-κB activation in keratinocytes in the development of psoriasis.

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...

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The novel inhibitory mechanism of thymol (2-isopropyl-5-methylphenol) on dopachrome formation by mushroom tyrosinase (EC 1.14.18.1) was identified. The UV-vis spectrum and oxygen consumption assays showed dopachrome formation using L-tyrosine as a substrate was suppressed by thymol. This inhibitory activity was reversed by the addition of a well-known radical scavenger, butylated hydroxyanisole (BHA). Further investigations using N-acetyl-L-tyrosine as a substrate with HPLC analysis suggested that thymol inhibits chemical redox reactions between dopaquinone and leukodopachrome instead of enzymatic reaction. This redox inhibitory activity of thymol was examined by using a model redox reaction with L-dihydroxyphenylalanine (L-DOPA) and p-benzoquinone. Thymol successfully inhibited oxidation of L-DOPA to dopaquinone, coupled with reduction of p-benzoquinone. Hence, the suppression of dopachrome formation by thymol is due to the inhibition of conversion of leukodopachrome to dopachrome. The antioxidant property of thymol is a key characteristic for the inhibitory mechanism of melanin synthesis.