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-NH 2, 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-NH 2 or
trypsin with IC 50 values 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-NH 2 and
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.