Glucocorticoid Receptor Counteracts Tumorigenic Activity of Akt in Skin through Interference with the Phosphatidylinositol 3-Kinase Signaling Pathway

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 18; no. 2; pp. 303 - 311
• Main Authors: Leis, Hugo, Page, Angustias, Ramírez, Angel, Bravo, Ana, Segrelles, Carmen, Paramio, Jesús, Barettino, Domingo, Jorcano, José L, Pérez, Paloma
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-02-2004; Oxford University Press
• Subjects: Administration, Topical; Animals; Carcinogenicity Tests; Cells, Cultured; Dexamethasone - administration & dosage; Dexamethasone - pharmacology; Female; Hormone Antagonists - pharmacology; I-kappa B Kinase; In Vitro Techniques; Keratinocytes - drug effects; Keratinocytes - metabolism; Mice; Mice, Nude; Mice, Transgenic; Mifepristone - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Signal Transduction; Skin - drug effects; Skin - metabolism; Skin - pathology
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2003-0350

The skin-targeted overexpression of the glucocorticoid receptor (GR) in transgenic mice dramatically impairs the inflammatory responses to tumor promoter agents and suppresses skin tumor development. The antiinflammatory, rapid effects of corticosteroids are partially exerted through interference of GR with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in several tissues, a highly relevant pathway in the mouse skin tumor progression process. In this work, we aimed to elucidate whether a cross-talk mechanism between GR and PI3K/Akt occurred in intact skin as well as the biological relevance of this interaction during skin tumorigenesis. We report that, in transgenic mice overexpressing the receptor, GR physically associated with p85α/PI3K in skin, resulting in decreased Akt and IκB kinase activity. GR activation by dexamethasone in normal mouse skin also decreased Akt activity within minutes, whereas cotreatment with the GR antagonist RU486 abolished dexamethasone action. Indeed, GR exerted a nongenomic action because keratinocyte transfection with a transcriptionally defective receptor mutant still decreased PI3K and Akt activity. Moreover, GR coexpression greatly reduced the accelerated growth of malignant tumors and increased Akt activity induced by Akt-transfected keratinocytes, as shown by in vivo tumorigenic assays. Overall, our data strongly indicate that GR/PI3K-Akt cross-talk constitutes a major mechanism underlying the antitumor effect of glucocorticoids in skin.