Abstract
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.
Highlights
Prostate cancer (PCa) remains a leading cause of death in men worldwide [1]
A tissue microarray study has shown that mechanistic target of rapamycin (mTOR) is up-regulated in PCa of all stages and grades [6]
Human endothelial cells were isolated from human umbilical veins and harvested by enzymatic treatment with dispase (Gibco/Invitrogen). They were grown in Medium 199 (M199; Biozol, Munich, Germany), supplemented with 10% fetal calf serum (FCS), 10% pooled human serum, 20 μg/mL endothelial cell growth factor (Boehringer, Mannheim, Germany), 0.1% heparin, 100 ng/mL gentamycin, and 20 mm HEPES buffer
Summary
Prostate cancer (PCa) remains a leading cause of death in men worldwide [1]. Once metastasized, PCa is difficult to treat and though androgen suppression prolongs survival it is not curative. A tissue microarray study has shown that mTOR is up-regulated in PCa of all stages and grades [6] It is thought, that targeting this pathway could lead to improved patient survival and therapeutic efficacy [7]. Combining an mTOR inhibitor with an HDAC inhibitor has been shown to exert synergistic effects on B-cell acute lymphoblastic leukemia, compared to isolated drug treatment [12]. Counteracting drug resistance encountered when treating different cancers by means of pharmacologic interaction with epigenetic machinery has been shown possible in vitro, in vivo, and in clinical studies [9,15,16,17]. The present study was designed to evaluate the effects of HDAC inhibition on the metastatic and invasive behavior of temsirolimus (TEM)-resistant prostate cancer cells
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