trans-Cinnamic acid, but not p-coumaric acid or methyl cinnamate, induces fibroblast migration through PKA- and p38-MAPK signalling pathways

Hydroxycinnamic acids their derivatives have various pharmacological properties. The hydroxycinnamic acid derivatives, methyl cinnamate, trans-cinnamic, and p-coumaric acids have been the object of study in the treatment of skin wounds. However, it is unclear whether these derivatives exert a direct beneficial effect on fibroblast function. In this study, we evaluated the effects of methyl cinnamate, trans-cinnamic, and p-coumaric acids on fibroblast migration in vitro.NIH 3T3 and L929 fibroblast cell lines were exposed to each drug at several concentrations and the effect on cell viability, cell cycle, and extracellular matrix production were assessed by MTT assay, flow cytometry, and immunofluorescence staining, respectively. The effect on cell migration was examined using scratch assay.The results showed that hydroxycinnamic acid derivatives not affect cell viability, but increase fibroblast migration in the in vitro scratch-wound healing assay. They also induced an increase in S and G2/M phases accompanied by a decrease in the G0/G1 phase of the cell cycle. The cell proliferation inhibitor mitomycin C abolished the effect induced by p-coumaric acid and methyl cinnamate, indicating that only the trans-cinnamic acid stimulated migration. A transwell migration assay confirmed that trans-cinnamic acid-treated fibroblasts exhibited increased migration compared with untreated cells. trans-Cinnamic acid-induced fibroblast migration was decreased by PKA inhibitor and p38-MAPK inhibitor but not by JNK inhibitor. Additionally, trans-cinnamic acid-treated fibroblasts showed an increase in the production of laminin and collagen type I.Our study showed that trans-cinnamic acid improves fibroblast migration and modulates extracellular matrix synthesis, indicating its potential for accelerating the healing process.