Valproic Acid Induces Neuroendocrine Differentiation and UGT2B7 Up-Regulation in Human Prostate Carcinoma Cell Line

Abstract

ABSTRACT:Prostate cancer originates as an androgen-dependent hyperproliferation of the epithelial cells of the gland and it evolves in an androgen-independent, highly aggressive cancer for which no successful therapy is available to date. Neuroendocrine (NE) differentiation plays an important role in the progression of prostate cancer to an androgen-independent state with profound impact on prostate cancer (CaP) therapies. Actually, new approaches on treating advanced prostate cancer are focused on modulators of epigenetic transcriptional regulation. A new class of antitumoral agents is emerging: histone deacetylase (HDAC) inhibitors are interesting for their ability to arrest cell growth, to induce cell differentiation, and in some cases, to induce apoptosis of cancer cells. We studied the effect of valproic acid (VPA), an inhibitor of HDAC, in the human prostate androgen-dependent cancer cell line LNCaP. We observed that VPA promotes neuroendocrine-like differentiation associated with an increase in the expression of neuron-specific enolase, a decrease in prostate-specific antigen, and a down-regulation of androgen receptor protein, suggesting a modulation in the responsiveness to androgen therapy. Furthermore, selective gene expression profiling using a low-density microarray showed that VPA was able to modulate the expression of different androgen metabolism genes. We observed a down-regulation of androgen receptor coregulator (ARA24) and prostatespecific antigen, and an up-regulation of some of the UDP-glucuronosyltransferases (UGT2B11 and UGT2B7) implicated in catabolism of dihydrotestosterone (DHT) was detected. Even though UGT2B7 has only about one-tenth to one-hundredth the activity of UGT2B15 and 2B17 toward active androgens and we did not found any modulation in gene expression of these enzymes, it can be hypothesized that VPA might enhance DHT catabolism in this in vitro model and induces NE differentiation. Our data seem to raise concern about CaP treatment with VPA.

Association of Uridine Diphosphate-Glucuronosyltransferase 2B Gene Variants with Serum Glucuronide Levels and Prostate Cancer Risk

“…, and UGT2B15 enzymes in the liver, skin, and prostate tissue (Turgeon et al, 2001;Chouinard et al, 2007;Valentini et al, 2007). Narrow black arrows indicate reversible catabolism of DHT; thick black arrows indicate irreversible production of testosterone-and DHT-G; gray arrows (on left and right) indicate irreversible production of ADT-G; and parallel black outlined arrows indicate irreversible production of AAG.…”

“…While several UGT2B7 variants have been described, they have not been examined in relation to prostate cancer (Turgeon et al, 2001;Menard et al, 2011). However, the expression of all three genes has been measured in prostate cancer cell lines (Valentini et al, 2007). The association of the UGT2B15 D85Y polymorphism with prostate cancer has been examined with conflicting results (MacLeod et al, 2000;Gsur et al, 2002;Hajdinjak and Zagradisnik, 2004;Park et al, 2004;Cunningham et al, 2007).…”

“…UGT2B15 and UGT2B17 conjugate AAG in the lumen and basal epithelial tissue of the prostate, respectively, and UGT2B7 also conjugates AAG in the skin ( Fig. 1) (Turgeon et al, 2001;Chouinard 1 et al, 2007;Valentini et al, 2007). A common genetic polymorphism in the UGT2B17 gene is gene deletion, and evidence shows that individuals who have two deleted UGT2B17 alleles secrete little-to-no urinary testosterone compared to individuals with at least one copy of the gene ( Jakobsson et al, 2006).…”

Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy

“…27 Androgen deprivation and chemical compounds were found to induce differentiation of neuroendocrine cells in prostate cancer. 28,29 All these studies suggest that the restoration of normal function or differentiated phenotypes in cancer cells is possible by the tumor-suppressive function of AgNPs.…”

Epigenetic regulation of the tissue-specific expression of human UDP-glucuronosyltransferase (UGT) 1A10

“…Previous studies have revealed that the expression of UGT1A6, UGT2B15, and UGT2B28 [20] as well as UGT2B7 and UGT2B11 [21], in cancer cell lines were increased by treatment with 5-Aza-dC or valproate, which is also a DNA methylation inhibitor. Although the DNA methylation status of these five UGT isoforms has not been investigated, the tissue-or cell-specific expression of most UGTs may be epigenetically regulated.…”