Sodium Salicylate Inhibits Urokinase Activity in MDA MB-231 Breast Cancer Cells

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Micro-AbstractWe investigated the effect of the anti-inflammatory drug, sodium salicylate, on urokinase plasminogen activator, a protease involved in metastasis and tumor invasion. Our results revealed concomitant urokinase activity inhibition and upregulation of its inhibitors, as well as cell-specific activation of the transforming growth factor-β pathway in triple-negative breast cancer cells. Sodium salicylate-induced downstream effectors of the transforming growth factor-β pathway could regulate the processes of breast cancer progression.Introduction:Sodium salicylate (NaS) is a derivate of acetylsalicylic acid or aspirin, used as a nonsteroidal anti-inflammatory drug for centuries, for its analgesic and anti-inflammatory effects. It was found to modulate different signaling pathways, in a cell-specific way. Here, we explore the effect of NaS on cell growth and urokinase activity in MDA MB-231 breast cancer cells.Materials and Methods:We analyzed the effect of NaS treatment on cell growth by flow cytometry and viability test. The transwell migration assay was used to study the migratory response of the cells. The gene expression was analyzed by qRT-PCR on RNA level and by Western blot analysis on protein level. Urokinase activity was assessed by caseinolysis.Results:Sublethal concentrations of NaS decreased cell growth and inhibited urokinase activity. The latter was a consequence of decrease in urokinase expression and increase in expression of its inhibitors. Analysis of signaling molecules revealed activation of transforming growth factor-β signaling, increase in master transcription factors for epithelial-mesenchymal transition and changes in integrin expression.Conclusions:We propose that NaS causes partial cellular reprogramming through transforming growth factor-β signaling which, together with direct NaS influence, causes changes in expression in a set of genes involved in extracellular proteolysis. These data could be beneficial for the development of new therapeutic approaches in invasive breast cancer treatment.

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