INVOLVEMENT OF RAS AND MAP KINASE (ERK-1) IN CISPLATIN-INDUCED ACTIVATION OF MURINE BONE-MARROW-DERIVED MACROPHAGES

Cisplatin (cis-diamminedichloroplatinum II), a potent antitumor compou nd, stimulates immune responses by activating monocytes/macrophages an d other cells of the immune system. However, the mechanism by which ci splatin activates these cells is poorly characterised. Our earlier fin dings indicate that cisplatin treatment stimulates rapid tyrosine phos phorylation in a number of cellular proteins in murine macrophages. Th is initial tyrosine phosphorylation is an important regulatory mechani sm and is followed by activation of several other proteins. In the pre sent study, we report the involvement of other key molecules and the r ole of tyrosine phosphorylation in their activation in the signaling c ascade of cisplatin. We observed the involvement of Pas (a low molecul ar weight GTP-binding protein) and ERK-1 (a MAP kinase) in-this signal ing cascade. Cisplatin treatment results in an increase in the express ion of both Ras and ERK-1 in a dose-dependent manner, which was depend ent upon tyrosine phosphorylation. Genistein a PTK inhibitor inhibited the cisplatin induced expression of Ras and ERK-1. These findings ind icate that Ras and ERK-1 are important signaling molecules involved in the tumoricidal activation of macrophages with cisplatin and is depen dent on initial tyrosine phosphorylation.