Apoptosis and differentiation induced by staurosporine in granulosa tumor cells is coupled with activation of JNK and suppression of p38 MAPK

We report here that staurosporine can induce apoptosis or differentiation of granulosa tumor cells depending on its dosage. In presence of staurosporine concentrations >50 nM, apoptosis was triggered in human granulosa cell tumor cells COV434. In the presence of concentrations <50 nM, the shape of the otherwise globular granulosa cells differentiated into a flattened epithelioid-like appearance. The process was associated by the induction of prostaglandin synthase-2 (PGS-2) and C/EBPB expression and by an increase in progesterone production in the supernatant culture medium. The observed effects of staurosporine were synergized by forskolin. With phosphorylation-specific Western blotting and protein kinase assays, it was demonstrated that staurosporine suppresses the phosphorylation of p38 and activates JNK. These results suggest that p38MAPK and JNK signal transduction pathways were involved in the regulation of granulosa cell differentiation by staurosporine. These results may indicate the usefulness of staurosporine or its analogs for the development of a future medical treatment of granulosa tumors.