HDAC inhibition counteracts metastatic re-activation of prostate cancer cells induced by chronic mTOR suppression

  • This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3res cells were enhanced following temsirolimus re-treatment. Integrin α and β receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell–matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3res cells. Blocking studies demonstrated a close association between α5 expression on PC3res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells.

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Author:Jasmina Makarević, Jochen RutzGND, Eva JüngelORCiDGND, Sebastian Maxeiner, Jens ManiGND, Stefan Vallo, Igor TsaurORCiDGND, Frederik RoosGND, Felix ChunORCiDGND, Roman A. BlahetaORCiD
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30200497
Parent Title (English):Cells
Place of publication:Basel
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/09/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/09/25
Tag:adhesion; histone deacetylase; integrins; invasion; mTOR; prostate cancer
Issue:9, Art. 129
Page Number:17
First Page:1
Last Page:17
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0