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HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A

BACKGROUND: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. METHODS: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (m...

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Autores principales: Juengel, Eva, Nowaz, Snigdha, Makarevi, Jasmina, Natsheh, Iyad, Werner, Isabella, Nelson, Karen, Reiter, Michael, Tsaur, Igor, Mani, Jens, Harder, Sebastian, Bartsch, Georg, Haferkamp, Axel, Blaheta, Roman A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073177/
https://www.ncbi.nlm.nih.gov/pubmed/24935000
http://dx.doi.org/10.1186/1476-4598-13-152
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author Juengel, Eva
Nowaz, Snigdha
Makarevi, Jasmina
Natsheh, Iyad
Werner, Isabella
Nelson, Karen
Reiter, Michael
Tsaur, Igor
Mani, Jens
Harder, Sebastian
Bartsch, Georg
Haferkamp, Axel
Blaheta, Roman A
author_facet Juengel, Eva
Nowaz, Snigdha
Makarevi, Jasmina
Natsheh, Iyad
Werner, Isabella
Nelson, Karen
Reiter, Michael
Tsaur, Igor
Mani, Jens
Harder, Sebastian
Bartsch, Georg
Haferkamp, Axel
Blaheta, Roman A
author_sort Juengel, Eva
collection PubMed
description BACKGROUND: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. METHODS: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Caki(res)), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins. RESULTS: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC(50). Akt and p70S6K, targets of everolimus, were activated in Caki(res) compared to drug sensitive cells. The most prominent change in Caki(res) cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Caki(res) cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Caki(res), evidenced by a significant decrease in tumor growth and cdk2/cyclin A. CONCLUSION: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
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spelling pubmed-40731772014-06-28 HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A Juengel, Eva Nowaz, Snigdha Makarevi, Jasmina Natsheh, Iyad Werner, Isabella Nelson, Karen Reiter, Michael Tsaur, Igor Mani, Jens Harder, Sebastian Bartsch, Georg Haferkamp, Axel Blaheta, Roman A Mol Cancer Research BACKGROUND: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. METHODS: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Caki(res)), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins. RESULTS: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC(50). Akt and p70S6K, targets of everolimus, were activated in Caki(res) compared to drug sensitive cells. The most prominent change in Caki(res) cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Caki(res) cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Caki(res), evidenced by a significant decrease in tumor growth and cdk2/cyclin A. CONCLUSION: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance. BioMed Central 2014-06-16 /pmc/articles/PMC4073177/ /pubmed/24935000 http://dx.doi.org/10.1186/1476-4598-13-152 Text en Copyright © 2014 Juengel et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Juengel, Eva
Nowaz, Snigdha
Makarevi, Jasmina
Natsheh, Iyad
Werner, Isabella
Nelson, Karen
Reiter, Michael
Tsaur, Igor
Mani, Jens
Harder, Sebastian
Bartsch, Georg
Haferkamp, Axel
Blaheta, Roman A
HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
title HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
title_full HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
title_fullStr HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
title_full_unstemmed HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
title_short HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
title_sort hdac-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin a
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073177/
https://www.ncbi.nlm.nih.gov/pubmed/24935000
http://dx.doi.org/10.1186/1476-4598-13-152
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