ECE2017 Eposter Presentations: Adrenal and Neuroendocrine Tumours Adrenal cortex (to include Cushing's) (86 abstracts)
Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells
Rosa Catalano 1, , Erika Peverelli 1, , Elena Giardino 1, , Donatella Treppiedi 1, , Valentina Morelli 1, , Iacopo Chiodini 1, , Lorenzo Marcon 1, , Cristina L Ronchi 3 , Jérôme Bertherat 4 , Felix Beuschlein 5 , Maura Arosio 1, , Anna Spada 1, & Giovanna Mantovani.
1Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; 2Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 3Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany; 4Institut Cochin, Inserm U1016, CNRS UMR8104, Descartes University, Department of Endocrinology, Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France; 5Medizinische Klinik und Poliklinik IV, Endocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany.
The cAMP signaling pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). In adrenocortical cells cAMP induces dramatic changes in cell morphology accompanied by actin cytoskeleton rearrangements that precede steroidogenesis, the causal relationship between these events being still undefined. In this study we investigated cAMP effects on cytoskeleton rearrangements and steroidogenic response in mouse (Y1) and human adrenocortical tumor cells, focusing on the role of the actin-severing protein cofilin, whose inactivation is regulated by phosphorylation on Ser3. Moreover, we tested possible alterations in cofilin phosphorylation status and expression in human CPA vs endocrine inactive adrenocortical adenomas (EIA). We demonstrated that forskolin induced cell rounding and reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (−52±16%, P<0.001) and primary human CPA cells (−53±18%, P<0.05). Cofilin silencing in Y1 cells reduced both forskolin-induced morphological changes (37±8% rounded cells vs 63±7% in control cells, P<0.05) and progesterone production (1.3-fold increase in silenced cells vs 1.8-fold in control cells, P<0.05), whereas transfection of wild type or S3A (active) cofilin, but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding (80±6% and 85±14% rounded cells, respectively, vs 69±6% in control cells) and increased about threefold progesterone synthesis with respect to control cells (P<0.05). Furthermore, cofilin dephosphorylation by Y27632, a selective inhibitor of ROCK, the kinase that phosphorylates cofilin, potentiated forskolin induced cell rounding (about 90% rounded cells) and steroidogenesis (about twofold increase vs forskolin alone).
Finally, western blot analysis showed a reduced P-cofilin/total cofilin ratio and an increased total cofilin expression in CPA vs EIA (P-cofilin/total cofilin ratio 0.76 and 2.44 respectively, P<0.05, total cofilin/GAPDH 1.20 and 0.54, respectively, P<0.01).
Overall, these data identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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