Radicicol, an inhibitor of Src-family
protein-tyrosine kinases, causes morphological reversion of v-src- and v-Ha-ras-transformed fibroblasts and arrest of the cell cycle at both the G1 and the G2 phases.
Radicicol was found to inhibit the growth of several other oncogene-transformed cell lines and human
carcinoma cell lines and to revert their cell morphology to be flat. In the
radicicol-treated flat cells, actin stress fiber bundles were reorganized. Since this effect of
radicicol on these cell lines was inhibited by
cycloheximide, de novo
protein synthesis is required for the morphological reversion. Screening of cellular
proteins enhanced in response to
radicicol by two-dimensional gel electrophoresis suggested that the amount of
gelsolin, an actin regulatory
protein, was distinctly increased upon
radicicol treatment. Western blot and Northern blot analyses showed that
radicicol enhanced transcription of the
gelsolin gene in human
carcinoma cell lines, as a result of which the amount of
gelsolin was increased several folds. Injection with an anti-
gelsolin antibody into cells and successive treatment with
radicicol resulted in approximately 80% reduction of the number of flat cells with stress fibers in comparison with controls treated with an irrelevant antibody. These results show that elevated expression of
gelsolin is associated, at least in part, with the suppression of transformation and the restoration of actin stress fibers in human
carcinoma cells by
radicicol.