title: Valproic acid induces neuroendocrine differentiation and UGT2B7 up-regulation in human prostate carcinoma cell line.
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 prostate-specific 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.
authors: Department of Internal Medicine-PTV, Consorzio interuniversitario per le Applicazioni di Supercalcolo Per Universitàe Ricerca (CASPUR), Rome, Italy. ales_valentini@yahoo.it
authors: Alessandra
authors: A
authors: Valentini
authors: Michela
authors: M
authors: Biancolella
authors: Francesca
authors: F
authors: Amati
authors: Paolo
authors: P
authors: Gravina
authors: Roberto
authors: R
authors: Miano
authors: Giovanni
authors: G
authors: Chillemi
authors: Alessio
authors: A
authors: Farcomeni
authors: Susana
authors: S
authors: Bueno
authors: Giuseppe
authors: G
authors: Vespasiani
authors: Alessandro
authors: A
authors: Desideri
authors: Giorgio
authors: G
authors: Federici
authors: Giuseppe
authors: G
authors: Novelli
authors: Sergio
authors: S
authors: Bernardini
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D009490:Neurosecretory Systems / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D011944:Receptors, Androgen; D014635:Valproic Acid; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D017430:Prostate-Specific Antigen; D010751:Phosphopyruvate Hydratase