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Cells 2018, 7(9), 129;

HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression

Department of Urology, Goethe-Universität Frankfurt, D-60590 Frankfurt am Main, Germany
Department of Urology and Pediatric Urology, University Medical Center Mainz, D-55131 Mainz, Germany
Author to whom correspondence should be addressed.
Received: 3 July 2018 / Revised: 28 August 2018 / Accepted: 30 August 2018 / Published: 1 September 2018
(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)
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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. View Full-Text
Keywords: mTOR; histone deacetylase; prostate cancer; integrins; adhesion; invasion mTOR; histone deacetylase; prostate cancer; integrins; adhesion; invasion

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Makarević, J.; Rutz, J.; Juengel, E.; Maxeiner, S.; Mani, J.; Vallo, S.; Tsaur, I.; Roos, F.; Chun, F.K.-H.; Blaheta, R.A. HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression. Cells 2018, 7, 129.

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