title: Teleocidin A2 inhibits human proteinase-activated receptor 2 signaling in tumor cells.
abstract: Enhanced expression of the proteinase-activated receptor 2 (PAR2) is linked to cell proliferation and migration in many cancer cell types. The role of PAR2 in cancer progression strongly illustrates the need for PAR2-inhibiting compounds. However, to date, potent and selective PAR2 antagonists have not been reported. The natural product teleocidin A2 was characterized against PAR2-activating peptide SLIGKV-NH2, and trypsin-induced PAR2-dependent intracellular Ca2+mobilization in tumor and in primary endothelial or epithelial cells. Further biochemical and cell-based studies were conducted to evaluate teleocidin specificity. The antagonizing effect of teleocidin A2 was confirmed in PAR2-dependent cell migration and rearrangement of actin cytoskeleton of human breast adenocarcinoma cell line (MDA-MB 231) breast cancer cells. Teleocidin A2 antagonizes PAR2-dependent intracellular Ca2+mobilization induced by either SLIGKV-NH2or trypsin with IC50values from 15 to 25 nmol/L in MDA-MB 231, lung carcinoma cell line, and human umbilical vein endothelial cell. Half maximal inhibition of either PAR1 or P2Y receptor-dependent Ca2+release is only achieved with 10- to 20-fold higher concentrations of teleocidin A2. In low nanomolar concentrations, teleocidin A2 reverses both SLIGKV-NH2and trypsin-mediated PAR2-dependent migration of MDA-MB 231 cells, and has no effect itself on cell migration and no effect on cell viability. Teleocidin A2 further controls PAR2-induced actin cytoskeleton rearrangement of MDA-MB 231 cells. Thus, for the first time, the small molecule natural product teleocidin A2 exhibiting PAR2 antagonism in the low nanomolar range with potent antimigratory activity is described.
authors.affiliation: Bio-Pharmaceutical Chemistry Faculty of Applied Natural Sciences Cologne University of Applied Sciences Chem Park Leverkusen Leverkusen Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Stahn
authors.affiliation: Bio-Pharmaceutical Chemistry Faculty of Applied Natural Sciences Cologne University of Applied Sciences Chem Park Leverkusen Leverkusen Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Thelen
authors.affiliation: Bio-Pharmaceutical Chemistry Faculty of Applied Natural Sciences Cologne University of Applied Sciences Chem Park Leverkusen Leverkusen Germany.
authors.forename: Ina-Maria
authors.initials: IM
authors.lastname: Albrecht
authors.affiliation: IMD Natural Solutions GmbH Dortmund Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bitzer
authors.affiliation: IMD Natural Solutions GmbH Dortmund Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Henkel
authors.affiliation: Bio-Pharmaceutical Chemistry Faculty of Applied Natural Sciences Cologne University of Applied Sciences Chem Park Leverkusen Leverkusen Germany.
authors.forename: Nicole Elisabeth
authors.initials: NE
authors.lastname: Teusch
keywords: Breast cancer; migration; proteinase‐activated receptor 2; teleocidin