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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 works that AQP3 is involved human skin fibroblast cell migration, we tested whether AQP3 is expressed in ovarian cancer line Caov3 and SKOV3 cells, and whether AQP3 expression in these cells enhances cell migration and metastatic potential. Our studies demonstrated that AQP3 is over-expressed in human ovarian cancer cell line Caov3 and SKOV3 cells. Our data, using specific AQP3 water transport inhibitors as well as siRNA knockdown, indicated that AQP3, or AQP3-mediated water transport, is involved in ovarian cell migration. EGF induced ovarian cancer cell migration, up-regulated AQP3 expression. EGF-induced cell migration was inhibited by AQP3 siRNA knockdown or by treatment with CuSO4 and NiCl2, both known as AQP3 water transport inhibitors. Mechanistic analysis suggests that EGFR activation is involved in EGF-induced AQP3 up-regulation and cell migration. Curcumin down-regulated AQP3 expression, and reduced cell migration in ovarian cancer cells. And the effects of curcumin were mediated, at least in part, by its inhibitory roles on EGFR activation. Collectively, our results provide evidence for AQP3-facilitated ovarian cancer cell migration, suggesting a novel function for AQP3 expression in high-grade tumors. [ABSTRACT FROM AUTHOR]

Overexpression of EGFR is associated with advanced-stage disease and poor prognosis of ovarian cancer, and activation of EGFR signaling pathway is involved in increased cell proliferation, angiogenesis, metastasis, and decreased apoptosis. Tyrosine kinase activity is essential for signal transduction and for receptor down-regulation. However, we found in this, study that tyrosine kinase activity is not necessary in ligand-induced EGFR down-regulation in Caov3 cells. EGFR tyrosine kinase inhibitors, such as PD153035, AG1478, as well as non-specific tyrosine kinase inhibitor PP2 did not reverse EGF-induced down-regulation of EGFR. These findings permit us to develop the following exciting but unconventional strategy, namely, priming ovarian cancer cell with EGF together with EGFR inhibitor PD153035. This priming down-regulates EGFR without induction of mitogenic signals. EGF plus EGFR inhibitor-primed ovarian cancer cells displayed more sensitive to Taxol-induced cell death and resistant to EGF-induced cell migration, cell proliferation as well as ERK, PI3K activation. Mechanistic analysis indicated that PD153035, which did not reverse ligand-induced EGFR down-regulation, blocked EGF-induced EGFR activation as well as EGFR binding with c-cb1 and Grb2. Taken together, we contend that combination of EGF priming with EGFR inhibitors would ultimately result in better chemotherapeutical outcome. [ABSTRACT FROM AUTHOR]