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Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma

Insights into the molecular and cellular biology of embryonal rhabdomyosarcoma (ERMS), an aggressive paediatric tumour, are required in order to identify new targets for novel treatments that may benefit patients with this disease. The present study examined the functional effects of MKK3 and MKK6,...

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Autores principales: Di Rocco, Agnese, Camero, Simona, Benedetti, Anna, Lozanoska-Ochser, Biliana, Megiorni, Francesca, Marchese, Cinzia, Stramucci, Lorenzo, Ciccarelli, Carmela, Bouché, Marina, Bossi, Gianluca, Marampon, Francesco, Zani, Bianca Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350981/
https://www.ncbi.nlm.nih.gov/pubmed/35801577
http://dx.doi.org/10.3892/or.2022.8363
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author Di Rocco, Agnese
Camero, Simona
Benedetti, Anna
Lozanoska-Ochser, Biliana
Megiorni, Francesca
Marchese, Cinzia
Stramucci, Lorenzo
Ciccarelli, Carmela
Bouché, Marina
Bossi, Gianluca
Marampon, Francesco
Zani, Bianca Maria
author_facet Di Rocco, Agnese
Camero, Simona
Benedetti, Anna
Lozanoska-Ochser, Biliana
Megiorni, Francesca
Marchese, Cinzia
Stramucci, Lorenzo
Ciccarelli, Carmela
Bouché, Marina
Bossi, Gianluca
Marampon, Francesco
Zani, Bianca Maria
author_sort Di Rocco, Agnese
collection PubMed
description Insights into the molecular and cellular biology of embryonal rhabdomyosarcoma (ERMS), an aggressive paediatric tumour, are required in order to identify new targets for novel treatments that may benefit patients with this disease. The present study examined the functional effects of MKK3 and MKK6, two upstream kinases of p38, and found that the ectopic expression of MKK6 led to rapid p38 activation and the myogenic differentiation of ERMS cells, whereas MKK3 failed to induce differentiation, while maintaining the proliferation state. Myogenin and myosin heavy chain were induced in MKK6-overexpressing ERMS cells and were inhibited by the p38 inhibitor, SB203580. The expression of Myc and ERK-PO4 increased under the effect of SB203580, whereas it decreased in MKK6-overexpressing cells. AKT activation was part of the myogenic program triggered by MKK6 overexpression alone. To the best of our knowledge, the present study demonstrates, for the first time, that the endogenous MKK6 pathway may be recovered by MEK/ERK inhibition (U0126 and trametinib) and that it concomitantly induces the reversal of the oncogenic pattern and the induction of the myogenic differentiation of ERMS cell lines. The effects of MEK/ERK inhibitors markedly increase the potential clinical applications in ERMS, particularly on account of the MEK inhibitor-induced early MKK6/p38 axis activation and of their anti-oncogenic effects. The findings presented herein lend further support to the antitumour effects of MKK6; MKK6 may thus represent a novel target for advanced personalised treatments against ERMS.
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spelling pubmed-93509812022-08-09 Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma Di Rocco, Agnese Camero, Simona Benedetti, Anna Lozanoska-Ochser, Biliana Megiorni, Francesca Marchese, Cinzia Stramucci, Lorenzo Ciccarelli, Carmela Bouché, Marina Bossi, Gianluca Marampon, Francesco Zani, Bianca Maria Oncol Rep Articles Insights into the molecular and cellular biology of embryonal rhabdomyosarcoma (ERMS), an aggressive paediatric tumour, are required in order to identify new targets for novel treatments that may benefit patients with this disease. The present study examined the functional effects of MKK3 and MKK6, two upstream kinases of p38, and found that the ectopic expression of MKK6 led to rapid p38 activation and the myogenic differentiation of ERMS cells, whereas MKK3 failed to induce differentiation, while maintaining the proliferation state. Myogenin and myosin heavy chain were induced in MKK6-overexpressing ERMS cells and were inhibited by the p38 inhibitor, SB203580. The expression of Myc and ERK-PO4 increased under the effect of SB203580, whereas it decreased in MKK6-overexpressing cells. AKT activation was part of the myogenic program triggered by MKK6 overexpression alone. To the best of our knowledge, the present study demonstrates, for the first time, that the endogenous MKK6 pathway may be recovered by MEK/ERK inhibition (U0126 and trametinib) and that it concomitantly induces the reversal of the oncogenic pattern and the induction of the myogenic differentiation of ERMS cell lines. The effects of MEK/ERK inhibitors markedly increase the potential clinical applications in ERMS, particularly on account of the MEK inhibitor-induced early MKK6/p38 axis activation and of their anti-oncogenic effects. The findings presented herein lend further support to the antitumour effects of MKK6; MKK6 may thus represent a novel target for advanced personalised treatments against ERMS. D.A. Spandidos 2022-07-08 /pmc/articles/PMC9350981/ /pubmed/35801577 http://dx.doi.org/10.3892/or.2022.8363 Text en Copyright: © Di Rocco et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Di Rocco, Agnese
Camero, Simona
Benedetti, Anna
Lozanoska-Ochser, Biliana
Megiorni, Francesca
Marchese, Cinzia
Stramucci, Lorenzo
Ciccarelli, Carmela
Bouché, Marina
Bossi, Gianluca
Marampon, Francesco
Zani, Bianca Maria
Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma
title Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma
title_full Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma
title_fullStr Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma
title_full_unstemmed Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma
title_short Anti-oncogenic and pro-myogenic action of the MKK6/p38/AKT axis induced by targeting MEK/ERK in embryonal rhabdomyosarcoma
title_sort anti-oncogenic and pro-myogenic action of the mkk6/p38/akt axis induced by targeting mek/erk in embryonal rhabdomyosarcoma
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350981/
https://www.ncbi.nlm.nih.gov/pubmed/35801577
http://dx.doi.org/10.3892/or.2022.8363
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