title: Signal transducer and activator of transcription-3 and phosphatidylinositol-3 kinase as coordinate regulators of melanoma cell response to glucocorticoid hormones.
abstract: 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.
authors.affiliation: Institute of Carcinogenesis, N.N. Blochin Cancer Research Center, Russian Academy of Medical Science, Kashirskoe shosse 24, Moscow 115478, Russia. mkras@mail.cnt.ru
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasil'nikov
authors.forename: Valentina
authors.initials: V
authors.lastname: Shatskaya
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D053614:Janus Kinase 2; D008156:Luciferases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D003907:Dexamethasone; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2