Evidence for mitogen-associated protein kinase activation and transductionof mitogenic signals by platelet-derived growth factor in human meningiomacells

Object. Coexpression of platelet-derived growth factor (PDGF)-BB and activa ted PDGF-beta receptor in meningioma cells indicates that this cytokine may act as an autocrine or paracrine stimulant of meningioma growth. The intra cellular events transducing signals from PDGF-beta receptor tyrosine kinase s are unknown. In this study the authors evaluated whether or not mitogen-a ctivated protein kinases (MAPKs) are expressed in meningiomas, regulate the ir growth, and transduce mitogenic signals of PDGF-BB. Methods. Ten human meningioma tumors as well as cells cultured from two nor mal leptomeninges and 10 additional human meningiomas were evaluated using Western blot analysis to determine the presence of MAPK and phosphorylated (activated) MAPK. The effects of PD098059, a selective inhibitor of MAPK ph osphorylation/activation, on proliferation of meningioma cells stimulated w ith 10% fetal bovine serum was also evaluated. Last, the authors evaluated whether PDGF-BB stimulation of meningioma cells was associated with activat ion of MAPK. Western blots of lysates from meningiomas and from cultured leptomeningeal and meningioma cells demonstrated MAPK and phosphorylated MAPK. Treatment w ith PD098059 produced a 52 to 84% (x = 69.8) loss in [H-3]thymidine incorpo ration, which was associated with a partial or complete loss of phosphoryla ted MAPK after 3 days of treatment. The PDGF-BB produced a significant incr ease in [H-3]thymidine incorporation and phosphorylation of MAPK at 1 and 3 days. Coadministration of PD098059 completely blocked PDGF-BB's stimulatio n of [H-3]thymidine incorporation and cell proliferation concomitant with r educed MAPK phosphorylation. Conclusions. The findings indicate that MAPK is constitutively expressed in leptomeningeal and meningioma cells and transduces mitogenic signals of PD GF, contributing to the growth of human meningiomas.