SCH 51344-INDUCED REVERSAL OF RAS-TRANSFORMATION IS ACCOMPANIED BY THE SPECIFIC-INHIBITION OF THE RAS AND RAC-DEPENDENT CELL MORPHOLOGY PATHWAY

RAS interacts with multiple targets in the cell and controls at least two signaling pathways, one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling fo rmation. These two pathways appear to act synergistically to cause: tr ansformation. SCH 51344 is a pyrazolo-quinoline derivative identified based on its ability to derepress transformation sensitive alpha-actin promoter in RAS-transformed cells, Previous studies have shown that S CH 51344 is a potent inhibitor of RAS-transformation, However, SCH 513 44 had very little effect on the activities of proteins in the ERI( pa thway, suggesting that it inhibits RAS-transformation by a novel mecha nism. In this study, we show that SCH 51344 specifically blocks membra ne ruffling induced by activated forms of H-RAS, II-RAS, N-RAS and RAG . Treatment of fibroblast cells with this compound had very little eff ect on RAS-mediated activation of ERK and JUN kinase activities. SCH 5 1344 was effective in inhibiting the anchorage-independent growth of R at-2 fibroblast cells transformed by the three forms of oncogenic RAS and RBC V12, These results indicate that SCH 51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and su ggest that targeting this pathway may be an effective approach to inhi bit transformation by RAS and other oncogenes.