TY  - JOUR
A1  - Makarević, Jasmina
A1  - Rutz, Jochen
A1  - Jüngel, Eva
A1  - Maxeiner, Sebastian
A1  - Mani, Jens
A1  - Vallo, Stefan
A1  - Tsaur, Igor
A1  - Roos, Frederik
A1  - Chun, Felix
A1  - Blaheta, Roman A.
T1  - HDAC inhibition counteracts metastatic re-activation of prostate cancer cells induced by chronic mTOR suppression
T2  - Cells
N2  - 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.
KW  - mTOR
KW  - histone deacetylase
KW  - prostate cancer
KW  - integrins
KW  - adhesion
KW  - invasion
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47112
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-471129
SN  - 2073-4409
N1  - 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).
VL  - 7
IS  - 9, Art. 129
SP  - 1
EP  - 17
PB  - MDPI
CY  - Basel
ER  -