Autotaxin (ATX) is a prometastatic
enzyme initially isolated from the conditioned media of
human melanoma cells that stimulates a myriad of biological activities including
angiogenesis and the promotion of
cell growth, survival, and differentiation through the production of
lysophosphatidic acid (LPA). ATX increases the aggressiveness and invasiveness of transformed cells, and ATX levels directly correlate with tumor stage and grade in several human malignancies. To study the role of ATX in the
pathogenesis of malignant
melanoma, we developed antibodies and
small molecule inhibitors against recombinant human
protein.
Immunohistochemistry of
paraffin embedded human tissue demonstrates that ATX levels are markedly increased in human primary and
metastatic melanoma relative to benign nevi. Chemical screens identified several
small molecule inhibitors with binding constants
ranging from nanomolar to low micromolar.
Cell migration and invasion assays with
melanoma cell lines demonstrate that ATX markedly stimulates
melanoma cell migration and invasion, an effect suppressed by ATX inhibitors. The migratory
phenotype can be rescued by the addition of ATX's enzymatic product, LPA, confirming that the observed inhibition is linked to suppression of LPA production by ATX. Chemical analogues of the inhibitors demonstrate structure activity relationships important for ATX inhibition and indicate pathways for their optimization. These studies suggest that ATX is an approachable molecular target for the
rational design of chemotherapeutic agents directed against human malignancies driven by the ATX / LPA axis, especially including malignant melanoma, among numerous others including breast and ovarian cancers.