Aquaporin‐1 inhibition reduces metastatic formation in a mouse model of melanoma

Abstract

Aquaporin-1 (AQP1) is a proangiogenic water channel protein promoting endothelial cell migration. We previously reported that AQP1 silencing by RNA interference reduces angiogenesis-dependent primary tumour growth in a mouse model of melanoma. In this study, we tested the hypothesis that AQP1 inhibition also affects animal survival and lung nodule formation. Melanoma was induced by injecting B16F10 cells into the back of C57BL6J mice. Intratumoural injection of AQP1 siRNA and CTRL siRNA was performed 10 days after tumour cell implantation. Lung nodule formation was analysed after the death of the mice. Western blot was used to quantify HIF-1a, caspase-3 (CASP3) and metalloproteinase-2 (MMP2) protein levels. We found that AQP1 knock-down (KD) strongly inhibited metastatic lung nodule formation. Moreover, AQP1 siRNA-treated mice showed a twofold survival advantage compared to mice receiving CTRL siRNAs. The reduced AQP1-dependent tumour angiogenesis caused a hypoxic condition, evaluated by HIF-1a significant increase, in turn causing an increased level of apoptosis in AQP1 KD tumours, assessed by CASP3 quantification and DNA fragmentation. Importantly, a decreased level of MMP2 after AQP1 KD indicated a decreased activity against extracellular matrix associated with reduced vascularization and metastatic formation. In conclusion, these findings highlight an additional role for AQP1 as an important determinant of tumour dissemination by facilitating tumour cell extravasation and metastatic formation. This study adds knowledge on the role played by AQP1 in tumour biology and supports the view of AQP1 as a potential drug target for cancer therapy.Keywords: aquaporin-1 tumour angiogenesis metastasis melanoma antiangiogenic therapy endothelial migration apoptosis extracellular matrix

AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

“…The "beneficial" role of AQP4-tetramers in glioma cells finds its basis in the functional role amply reported for M1-AQP4 in favoring cell migration both in healthy astrocytes and in glioma cells (41)(42)(43). It is interesting to note that the role for M1-AQP4 in cell migration in the context of glioma cell invasiveness is remarkably similar to the role of AQP1 in endothelial cell migration in the context of tumor angiogenesis (44). Notably, AQP1 is only expressed in the tetrameric form.…”

Inhibitors of Mammalian Aquaporin Water Channels

“…Aquaporins (AQPs) are transmembrane proteins that facilitate the bidirectional transport of water across cell membranes; water flows through AQP pores following an osmotic gradient to support water homeostasis [1,2,3]. A subset of the AQP family, the aquaglyceroporins, also allows the transport of glycerol and other small neutral solutes such as urea and ammonia [4,5,6,7].…”

Inhibitory effect of AQP1 silencing on adhesion and angiogenesis in ectopic endometrial cells of mice with endometriosis through activating the Wnt signaling pathway

“…Considering cell apoptosis, in this present study, AQP1 silencing promoted apoptosis of ectopic endometrial cells, which was determined by the elevated expression of apoptosis-related factors (Caspase-3, Caspase-9, and Bax) as well as the reduced expression of BcL-2. A previous study demonstrated that, in line with DNA fragmentation analysis, depleted AQP1-dependent angiogenesis induced cell apoptosis in tumors [34]. In another study, the author confirmed that the AQP1 inhibitor-bacopaside II inhibited the viability, migration and tube formation of endothelial cells, and enhanced apoptosis [35].…”