Background/Aims: Due to its antitumor and gastroprotective properties, cochinchina momordica seed (CMS), has been widely used to treat cancer patients in Asia. Our previous reports have shown that CMS is able to induce the differentiation of B16-F1 melanoma cells. However, its functional component and mechanism remain unclear and are addressed in this study. Methods and Results: CMSP (p-hydroxycinnamaldehyde isolated from CMS) inhibited the proliferation, migration and invasiveness of B16-F1 cells both in vivo and in vitro. CMSP also induced the differentiation of B16-F1 cells, as characterized by dendrite-like outgrowth, increased melanogenesis and enhanced tyrosinase activity. Furthermore, CMSP treatment reduced the level of malignant markers of melanoma, specifically S-100B and melanoma derived growth regulatory protein precursor (MIA), in a concentration -dependent manner According to a western blot analysis, B16-F1 cells treated with CMSP exhibited a sustained increase in p-P38 and decreased activities of FRK and JN K. Our data further indicated that the downregulation of GTP-RhoA, which was mediated by increased cAMP release, was involved in CMSP-induced changes in MAPK. while LPA (Lysophosphatidic acid) partially reversed CMSP-induced B16 cell differentiation. Conclusion: These results demonstrated that CMSP-induced differentiation of Bl6F1 cells may occur through the RhoA-MAPK axis, which suggests a new potential strategy for melanoma treatment. Copyright (C) 2016 S. Karger AG, Basel