{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T04:16:45Z","timestamp":1773116205883,"version":"3.50.1"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,9,1]],"date-time":"2018-09-01T00:00:00Z","timestamp":1535760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 \u03b1 and \u03b2 receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell\u2013matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin \u03b15 in PC3res cells. Blocking studies demonstrated a close association between \u03b15 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 \u03b15 surface level on the tumor cells.<\/jats:p>","DOI":"10.3390\/cells7090129","type":"journal-article","created":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T10:50:51Z","timestamp":1535971851000},"page":"129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression"],"prefix":"10.3390","volume":"7","author":[{"given":"Jasmina","family":"Makarevi\u0107","sequence":"first","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen","family":"Rutz","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Juengel","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"},{"name":"Department of Urology and Pediatric Urology, University Medical Center Mainz, D-55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Maxeiner","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Mani","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Vallo","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Tsaur","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"},{"name":"Department of Urology and Pediatric Urology, University Medical Center Mainz, D-55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix K.-H.","family":"Chun","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman A.","family":"Blaheta","sequence":"additional","affiliation":[{"name":"Department of Urology, Goethe-Universit\u00e4t Frankfurt, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21442","article-title":"Cancer statistics, 2018","volume":"68","author":"Siegel","year":"2018","journal-title":"CA Cancer J. 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