Radicicol suppresses transformation and restores tropomyosin-2 expression in both ras- and MEK-transformed cells without inhibiting the Raf/MEK/ERK signaling cascade

The antibiotic radicicol suppresses transformation in a variety of transfor med cells. The antineoplastic effects of the drug have been attributed to t he degradation of Raf and the inactivation of the Ras/Raf/ mitogen-activate d protein kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK) signaling cascade. Here we demonstrate that radicicol induces cell spreadin g, suppresses anchorage-independent cell growth, and increases the expressi on of the high-molecular weight tropomyosin isoform TM-2 in cells stably ex pressing a constitutively active form of MEK-1 as well as in ras-transforme d cells. Furthermore, the reverting effects of the drug are achieved at con centrations below those required to deplete Raf from the cell or to inhibit the phosphorylation of ERK or its substrates Elk and pp90(RSK). In contras t, low concentrations of radicicol significantly inhibited activator protei n (AP-1) and serum response factor (SRF)-mediated transcription. The lack o f correlation between the effects of radicicol on cell phenotype and on the signaling activities of the Raf/MEK/ERK pathway indicate that Raf depletio n or disruption of proximal signaling events in the mitogen:activated prote in kinase pathway are not the predominant mechanisms by which the drug supp resses the transformed phenotype. Our observation that low concentrations o f radicicol block transcriptional activities mediated by AP-1 and SRF sugge sts that interference with signaling upstream of these transcription factor s may contribute to the reverting effects of the drug.