Decreased tissue plasminogen activator and increased plasminogen activatorinhibitors and increased activator protein-1 and specific promoter 1 are associated with inhibition of invasion in human A375 melanoma deprived of tyrosine and phenylalanine

We previously found that dietary tyrosine (Tyr) and phenylalanine (Phe) res triction significantly decreased the metastatic phenotype of the pigmented murine B16BL6 melanoma in vivo and decreased the in vitro invasion of these cells. Here we report that invasion and chemoinvasion through GFR Matrigel of the human amelanotic A375 melanoma also is significantly inhibited by T yr and Phe deprivation in vitro. Deprivation of these two amino acids decre ased the secretion and protein expression of tissue-type plasminogen activa tor (tPA) while expression and secretion of plasminogen activator inhibitor (PAI-1 and PAI-2) were increased. Moreover, nuclear extracts of Tyr- and P he-deprived cells exhibited increased binding of the transcription factors, activator protein-1 (AP-1) and specific promoter-1 (Spl), to consensus oli gonucleotides as determined by electrophoretic mobility shift assay. Nuclea r binding activity to the oligonucleotide consensus sequence for AP-1 was i nhibited by antibody against c-Fos and more effectively inhibited by an ant ibody against c-Jun. We conclude that decreased invasion and chemoinvasion of A375 melanoma cells deprived of Tyr and Phe are related to decreased sec retion of tPA and increased secretion of PAIs. Increased AP-1 and Spl bindi ng implicates these transcription factors in the regulation of PAI expressi on.