title: NFAT5/STAT3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells.
abstract: Chronic inflammation has been considered an important player in cancer proliferation and progression. High salt (sodium chloride) levels have been considered a potent inducer of chronic inflammation. In the present study, the synergistic role of high salt with interleukin (IL)-17 towards induction of the inflammatory and angiogenic stress factor vascular endothelial growth factor (VEGF)-A was investigated. Stimulation of MCF-7 breast cancer cells with high salt (0.2 M NaCl) and sub-minimal IL-17 (1 ng/ml) enhanced the expression of VEGF-A (2.9 and 2.6-fold, respectively, P<0.05) compared with untreated cells. Furthermore, co-treatment with both high salt and sub-minimal IL-17 led to a 5.9-fold increase in VEGF-A expression (P<0.01), thus suggesting a synergistic role of these factors. VEGF-A promoter analysis and specific small interfering RNA knock-down of transcription factors revealed that high salt induced VEGF-A expression through nuclear factor of activated T-cells (NFAT)5, while IL-17 induced VEGF-A expression via signal transducer and activator of transcription (STAT)3 signaling mechanisms. Treatment of normal human aortic endothelial cells with the supernatant of activated MCF-7 cells enhanced cell migration and induced expression of migration-specific factors, including vascular cell adhesion protein, β1 integrin and cluster of differentiation 31. These data suggest that high salt levels synergize with pro-inflammatory IL-17 to potentially induce cancer progression and metastasis through VEGF-A expression. Therefore, low-salt diet, anti-NFAT5 and anti-STAT3 therapies may provide novel avenues for enhanced efficiency of the current cancer therapy.
authors.affiliation: Department of Medicine, Mercy Hospital, St. Louis, MO 63141, USA.
authors.forename: Suneetha
authors.initials: S
authors.lastname: Amara
authors.affiliation: Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA.
authors.forename: Dalal
authors.initials: D
authors.lastname: Alotaibi
authors.affiliation: Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA.
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
keywords: NFAT5; breast cancer; cell migration; inflammation; interleukin-17