Inhibition of B16BL6 melanoma invasion by tyrosine and phenylalanine deprivation is associated with decreased secretion of plasminogen activators andincreased plasminogen activator inhibitors

We previously found that dietary tyrosine (Tyr) and phenylalanine (Phe) lim itation significantly decreased the metastatic phenotype of B16BL6 melanoma cells in vivo and decreased the in vitro invasion of these cells. To more specifically characterize the effects of Tyr and Phe deprivation we examine d the three steps involved in invasion: attachment to host cells and compon ents, elaboration of proteases that degrade basement membranes, and migrati on of invading tumor cells. Here we report that B16BL6 melanoma cell invasi on through growth factor reduced (GFR) Matrigel(TM) is significantly decrea sed by Tyr and Phe deprivation. Tyr and Phe deprivation in vitro decreased the attachment of B16BL6 melanoma cells to GFR Matrigel(TM), heparin sulfat e proteoglycans (HSPG), neonatal murine epidermal (NME) cells and the extra cellular matrix (ECM) from these cells. These cells also exhibited a decrea se in chemotactic response to fetal bovine serum (FBS). Deprivation of thes e two amino acids decreased the secretion of urokinase plasminogen activato r (uPA) and tissue plasminogen activator (tPA) while plasminogen activator inhibitor (PAI)-1 and -2 were increased in these cells. These observations suggest that Tyr and Phe deprivation decreases the in vitro chemotactic and invasive ability of B16BL6 melanoma cells by decreasing attachment and sec reted PA activity and by increasing secreted PAIs in these cells.