Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling

Mycophenolate Mofetil (MYC) is a transplant drug used to prevent rejection in heart and kidneys transplant patients. Inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in de novo synthesis of guanosine nucleotides, was considered as a primary target for MYC. Recently, we described that...

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Autores principales: Zenata, Ondrej, Dvorak, Zdenek, Vrzal, Radim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995952/
https://www.ncbi.nlm.nih.gov/pubmed/29896275
http://dx.doi.org/10.7150/jca.23648
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author Zenata, Ondrej
Dvorak, Zdenek
Vrzal, Radim
author_facet Zenata, Ondrej
Dvorak, Zdenek
Vrzal, Radim
author_sort Zenata, Ondrej
collection PubMed
description Mycophenolate Mofetil (MYC) is a transplant drug used to prevent rejection in heart and kidneys transplant patients. Inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in de novo synthesis of guanosine nucleotides, was considered as a primary target for MYC. Recently, we described that MYC was activates aryl hydrocarbon receptor and it antagonizes glucocorticoid receptor. Here we describe an androgen receptor (AR) as another off-target for MYC. We found that MYC increased basal and dihydrotestosterone (DHT)-inducible AR-dependent luciferase activity in AIZ-AR cells. In the same manner it induced or augmented mRNA level of KLK3 (prostate specific antigen; PSA) in 22Rv1 cells. Herein it displayed a hormetic effect on proliferation activity, since it significantly stimulated proliferation in lower concentrations but inhibited in higher (>1 µg/ml) concentrations in the presence of DHT. In contrast, MYC suppressed DHT-inducible KLK3 mRNA expression and cell proliferation in androgen-dependent LNCaP cells. MYC augmented DHT-inducible nuclear translocation of AR and increased the expression of MAPK8/9 (JNK46/54) resulting in the drop of their phosphorylation status. Moreover, MYC sensitized DHT-treated 22Rv1 cells to JNK-IN-8 mediated growth inhibition with the drop of IC(50) from 1425 nM to 84 nM within 24 hrs. In conclusion, we suggest that, castrate-resistant prostate cancers progression might be retarded with the combination of MYC and chemical JNK inhibitors, involving AR-dependent mechanism.
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spelling pubmed-59959522018-06-12 Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling Zenata, Ondrej Dvorak, Zdenek Vrzal, Radim J Cancer Research Paper Mycophenolate Mofetil (MYC) is a transplant drug used to prevent rejection in heart and kidneys transplant patients. Inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in de novo synthesis of guanosine nucleotides, was considered as a primary target for MYC. Recently, we described that MYC was activates aryl hydrocarbon receptor and it antagonizes glucocorticoid receptor. Here we describe an androgen receptor (AR) as another off-target for MYC. We found that MYC increased basal and dihydrotestosterone (DHT)-inducible AR-dependent luciferase activity in AIZ-AR cells. In the same manner it induced or augmented mRNA level of KLK3 (prostate specific antigen; PSA) in 22Rv1 cells. Herein it displayed a hormetic effect on proliferation activity, since it significantly stimulated proliferation in lower concentrations but inhibited in higher (>1 µg/ml) concentrations in the presence of DHT. In contrast, MYC suppressed DHT-inducible KLK3 mRNA expression and cell proliferation in androgen-dependent LNCaP cells. MYC augmented DHT-inducible nuclear translocation of AR and increased the expression of MAPK8/9 (JNK46/54) resulting in the drop of their phosphorylation status. Moreover, MYC sensitized DHT-treated 22Rv1 cells to JNK-IN-8 mediated growth inhibition with the drop of IC(50) from 1425 nM to 84 nM within 24 hrs. In conclusion, we suggest that, castrate-resistant prostate cancers progression might be retarded with the combination of MYC and chemical JNK inhibitors, involving AR-dependent mechanism. Ivyspring International Publisher 2018-04-27 /pmc/articles/PMC5995952/ /pubmed/29896275 http://dx.doi.org/10.7150/jca.23648 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zenata, Ondrej
Dvorak, Zdenek
Vrzal, Radim
Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling
title Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling
title_full Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling
title_fullStr Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling
title_full_unstemmed Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling
title_short Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling
title_sort mycophenolate mofetil induces c-jun-n-terminal kinase expression in 22rv1 cells: an impact on androgen receptor signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995952/
https://www.ncbi.nlm.nih.gov/pubmed/29896275
http://dx.doi.org/10.7150/jca.23648
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