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Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells

To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT)...

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Autores principales: Fliedner, Stephanie M. J., Engel, Tobias, Lendvai, Nikoletta K., Shankavaram, Uma, Nölting, Svenja, Wesley, Robert, Elkahloun, Abdel G., Ungefroren, Hendrik, Oldoerp, Angela, Lampert, Gary, Lehnert, Hendrik, Timmers, Henri, Pacak, Karel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028222/
https://www.ncbi.nlm.nih.gov/pubmed/24846270
http://dx.doi.org/10.1371/journal.pone.0097712
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author Fliedner, Stephanie M. J.
Engel, Tobias
Lendvai, Nikoletta K.
Shankavaram, Uma
Nölting, Svenja
Wesley, Robert
Elkahloun, Abdel G.
Ungefroren, Hendrik
Oldoerp, Angela
Lampert, Gary
Lehnert, Hendrik
Timmers, Henri
Pacak, Karel
author_facet Fliedner, Stephanie M. J.
Engel, Tobias
Lendvai, Nikoletta K.
Shankavaram, Uma
Nölting, Svenja
Wesley, Robert
Elkahloun, Abdel G.
Ungefroren, Hendrik
Oldoerp, Angela
Lampert, Gary
Lehnert, Hendrik
Timmers, Henri
Pacak, Karel
author_sort Fliedner, Stephanie M. J.
collection PubMed
description To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.
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spelling pubmed-40282222014-05-21 Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells Fliedner, Stephanie M. J. Engel, Tobias Lendvai, Nikoletta K. Shankavaram, Uma Nölting, Svenja Wesley, Robert Elkahloun, Abdel G. Ungefroren, Hendrik Oldoerp, Angela Lampert, Gary Lehnert, Hendrik Timmers, Henri Pacak, Karel PLoS One Research Article To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread. Public Library of Science 2014-05-20 /pmc/articles/PMC4028222/ /pubmed/24846270 http://dx.doi.org/10.1371/journal.pone.0097712 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Fliedner, Stephanie M. J.
Engel, Tobias
Lendvai, Nikoletta K.
Shankavaram, Uma
Nölting, Svenja
Wesley, Robert
Elkahloun, Abdel G.
Ungefroren, Hendrik
Oldoerp, Angela
Lampert, Gary
Lehnert, Hendrik
Timmers, Henri
Pacak, Karel
Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells
title Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells
title_full Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells
title_fullStr Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells
title_full_unstemmed Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells
title_short Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells
title_sort anti-cancer potential of mapk pathway inhibition in paragangliomas–effect of different statins on mouse pheochromocytoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028222/
https://www.ncbi.nlm.nih.gov/pubmed/24846270
http://dx.doi.org/10.1371/journal.pone.0097712
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