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

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.

Resistance to targeted treatment of gastroenteropancreatic neuroendocrine tumors

“…Epigenetic modifications seem to be involved in therapy resistance through transcriptional silencing of target components or activation of rescue pathways (Berdasco & Esteller 2010, Kelly et al 2010, Wilting & Dannenberg 2012, Hervouet et al 2013. In prostate cancer cell lines, the histone deacetylase (HDAC) inhibitor valproic acid has been shown to overcome resistance to temsirolimus, a rapalog (Makarević et al 2018). Moreover, valproic acid acetylates histone variants H3 and H4 in temsirolimusresistant bladder cancer and in everolimus-resistant renal cancer cells (Juengel et al 2012(Juengel et al , 2014(Juengel et al , 2017.…”

Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

“…HDAC inhibition has also been shown to induce a strong response of temsirolimus-resistant bladder and RCC cancer cells [13,14]. Resistance to temsirolimus is associated with increased adhesion and migration of prostate cancer cells, which could be reverted by down-regulating HDAC [15].…”

Inhibition of lipogenesis and induction of apoptosis by valproic acid in prostate cancer cells via the C/EBPα/SREBP-1 pathway

“…The incidence of PCa exhibits an increasing trend in recent years. Previous studies indicated that VPA is a potential suppressor of the growth of PCa cells [10,13,16]. To test whether the growth inhibition was dose dependent, PC-3 cells were treated with different concentrations of VPA (ranging from 0.5 to 10.0 mM) for 4 days, followed by the MTT cell viability assay.…”

“…Recent studies have shown that VPA can suppress the malignancy of various cancers including prostate cancer, glioblastoma, and melanoma because it inhibits tumor growth and metastasis, induces differentiation and apoptosis, and enhances chemotherapy sensitivity [10][11][12]. Although a study indicates that VPA pretreatment suppresses PCa cell viability [13], its potential roles and, more importantly, the underlying mechanisms of its actions have not been extensively studied.…”