cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (−52 ± 16%, p < 0.001) and human CPA cells (−53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.

Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells / E. Peverelli, R. Catalano, E. Giardino, D. Treppiedi, V. Morelli, C.L. Ronchi, A. Vaczlavik, N. Fusco, S. Ferrero, J. Bertherat, F. Beuschlein, I. Chiodini, M. Arosio, A. Spada, G. Mantovani. - In: CANCER LETTERS. - ISSN 0304-3835. - 406(2017 Oct), pp. 54-63. [10.1016/j.canlet.2017.07.025]

Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells

E. Peverelli
;
R. Catalano;E. Giardino;D. Treppiedi;V. Morelli;C.L. Ronchi;N. Fusco;I. Chiodini;M. Arosio;G. Mantovani
2017

Abstract

cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (−52 ± 16%, p < 0.001) and human CPA cells (−53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.
Adrenocortical adenomas; cAMP; Cofilin; Cortisol; Cytoskeleton; Actin Cytoskeleton; Actin Depolymerizing Factors; Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Animals; Colforsin; Cyclic AMP; Humans; Hydrocortisone; Mice; Phosphorylation; RNA, Small Interfering; Steroids; Tumor Cells, Cultured; Vasodilator Agents; Oncology; Cancer Research
Settore MED/13 - Endocrinologia
Settore MED/08 - Anatomia Patologica
Article (author)
File in questo prodotto:
File Dimensione Formato  
[2017] [Cancer Letters] Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells.pdf

accesso aperto

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 2.3 MB
Formato Adobe PDF
2.3 MB Adobe PDF Visualizza/Apri
1-s2.0-S0304383517304615-main.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 2.14 MB
Formato Adobe PDF
2.14 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/608525
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 8
social impact