Ji Chao, Cao Cong, Lu Shan, Kivlin Rebecca, Amaral Ashley, Kouttab Nicola, Yang Hui, Chu Wenming, Bi Zhigang, Di Wen, Wan Yinsheng
Department of Biology, Providence College, 549 River Ave, Providence, RI 02918, USA.
Cancer Chemother Pharmacol. 2008 Oct;62(5):857-65. doi: 10.1007/s00280-007-0674-6. Epub 2008 Jan 23.
Aquaporin (AQP) water channels are expressed in high-grade tumor cells of different tissue origins. Based on the involvement of AQPs in angiogenesis and cell migration as well as our previous studies which show that AQP3 is involved in human skin fibroblasts cell migration, in this study, we investigated whether AQP3 is expressed in cultured human ovarian cancer cell line CaOV3 cells, and whether AQP3 expression in these cells enhances cell migration and metastatic potential.
Cultured CaOV3 cells were treated with EGF and/or various reagents and subjected to cell migration assay by phagokinetic track mobility assay or biochemical analysis for expression or activation of proteins by SDS-PAGE/Western blot analysis.
In this study, we demonstrate that AQP3 is expressed in CaOV3 cells. EGF induces CaOV3 migration and up-regulates AQP3 expression. EGF-induced cell migration is inhibited by specific AQP3 siRNA knockdown or AQP3 water transport inhibitor CuSO4 and NiCl2. We also find that curcumin, a well known anti-ovarian cancer drug, down-regulates AQP3 expression and reduces cell migration in CaOV3, and the effects of curcumin are mediated, at least in part, by its inhibitory effects on EGFR and downstream AKT/ERK activation.
Collectively, our results provide evidence for AQP3-facilitated ovarian cancer cell migration, suggesting a novel function for AQP3 expression in high-grade tumors. The results that curcumin inhibits EGF-induced up-regulation of AQP3 and cell migration, provide a new explanation for the anticancer potential of curcumin.
水通道蛋白（AQP）水通道在不同组织来源的高级别肿瘤细胞中表达。基于水通道蛋白参与血管生成和细胞迁移，以及我们之前的研究表明水通道蛋白3参与人皮肤成纤维细胞迁移，在本研究中，我们调查了水通道蛋白3是否在培养的人卵巢癌细胞系CaOV3细胞中表达，以及这些细胞中该蛋白的表达是否增强细胞迁移和转移潜能。
用表皮生长因子（EGF）和/或各种试剂处理培养的CaOV3细胞，并通过吞噬动力学轨迹迁移试验进行细胞迁移测定，或通过SDS-PAGE/蛋白质免疫印迹分析对蛋白质表达或激活进行生化分析。
在本研究中，我们证明水通道蛋白3在CaOV3细胞中表达。EGF诱导CaOV3细胞迁移并上调水通道蛋白3的表达。特异性水通道蛋白3的小干扰RNA敲低或水通道蛋白3水转运抑制剂硫酸铜和氯化镍可抑制EGF诱导的细胞迁移。我们还发现，姜黄素，一种著名的抗卵巢癌药物，可下调CaOV3细胞中水通道蛋白3的表达并减少细胞迁移，且姜黄素的作用至少部分是通过其对表皮生长因子受体（EGFR）和下游AKT/细胞外信号调节激酶（ERK）激活的抑制作用介导的。
总的来说，我们的结果为水通道蛋白3促进卵巢癌细胞迁移提供了证据，提示了水通道蛋白3在高级别肿瘤中表达的新功能。姜黄素抑制EGF诱导的水通道蛋白3上调和细胞迁移的结果，为姜黄素的抗癌潜力提供了新的解释。
