Signal transducer and activator of transcription-3 and phosphatidylinositol-3 kinase as coordinate regulators of melanoma cell response to glucocorticoid hormones.

STAT proteins act as signal transducers and activators of transcription in cells treated with cytokines or growth factors. Here we analyzed the possible cooperation between STAT3 and phosphatidylinositol-3 kinase (PI-3 kinase) and its involvement in antiproliferative signals induced by glucocorticoid hormones. Treatment of melanoma cells with dexamethasone (DEX) resulted in coexpression of STAT3 activation and increase in the PI-3 kinase protein level. Using plasmids-containing JAK2 and STAT3 constructs, we demonstrated that activation of JAK/STAT signaling led to up regulation of PI-3 kinase and enhancement of DEX's ability to increase PI-3 kinase levels in target cells. Prolonged DEX treatment of melanoma cells resulted in constitutive increases in both STAT3 and PI-3 kinase protein levels that were correlated with increased melanoma resistance to antiproliferative hormone action. Similarly, forced expression of both STAT3 and PI-3 kinase in melanoma cells led to enhanced resistance to hormone treatment. Forced expression of PI-3 kinase led to increase in STAT3 activity in a JAK-dependent manner, indicating the existence of a feedback regulatory cascade between the JAK/STAT3 and PI-3 kinase pathways. We suggest that protection of melanoma cells from antiproliferative effects of glucocorticoid hormones may be mediated, at least in part, by the constitutive activation of the STAT3/PI-3 kinase signaling pathway.