K252A INHIBITS PROLIFERATION OF GLIOMA-CELLS BY BLOCKING PLATELET-DERIVED GROWTH-FACTOR SIGNAL-TRANSDUCTION

Growth factors are known to regulate glioma proliferation, The glioma cell lines U87 and T98G were examined for evidence of an autocrine sti mulatory loop involving the neurotrophin family of growth factors. Alt hough neurotrophin-3 and TrkC RNA were detected by reverse transcripti on-PCR, there was no evidence of significant interaction between neuro trophin-3 and its cognate receptor TrkC, The microbial alkaloid K252a has been described to inhibit both Trk tyrosine kinase activity and ne uroblastoma cell proliferation. K252a inhibited proliferation in U87 ( IC50 = 1170 nM) and T98G (IC50 = 529 nM) but induced apoptosis in U87 cells only. At concentrations of 500 nM to 1 mu M, K252a blocked only platelet-derived growth factor (PDGF)-mediated receptor autophosphoryl ation. These results suggest that an autocrine loop involving PDGF is functional and important for maintaining tumor growth. There is no evi dence to support the existence of a neurotrophin-mediated autocrine lo op, K252a, through inhibition of PDGF signal transduction, may be a no vel therapeutic agent in the treatment of human gliomas.