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 RC
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 (Cakires), 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 IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires 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 Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, 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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Author:Eva Jüngel, Snigdha Nowaz, Jasmina Makarevi, Iyad Y. M. Natsheh, Isabella Werner, Karen Nelson, Michael Reiter, Igor Tsaur, Jens Mani, Sebastian Harder, Georg Bartsch, Axel Haferkamp, Roman A. Blaheta
URN:urn:nbn:de:hebis:30:3-352882
DOI:http://dx.doi.org/10.1186/1476-4598-13-152
ISSN:1476-4598
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24935000
Parent Title (English):Molecular cancer
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2014/11/04
Date of first Publication:2014/06/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/11/04
Tag:Everolimus resistance; HDAC-inhibition; Renal cell carcinoma; Tumor growth; cdk2/cyclin A
Volume:13
Issue:152
Pagenumber:10
Note:
© 2014 Juengel et al.; licensee BioMed Central Ltd. 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.
HeBIS PPN:366633023
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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