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Drug Metabolism and Disposition Fast Forward
First published on March 19, 2007; DOI: 10.1124/dmd.107.014662

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Received for publication January 10, 2007.
Revised March 14, 2007.
Accepted for publication March 15, 2007.

Valproic acid induces neuroendocrine differentiation and UGT2B7 up-regulation in human prostate carcinoma cell line

Alessandra Valentini 1*, Michela Biancolella 1, Francesca Amati 1, Paolo Gravina 1, Roberto Miano 1, Giovanni Chillemi 2, Alessio Farcomeni 2, Susana Bueno 2, Giuseppe Vespasiani 1, Alessandro Desideri 1, Giorgio Federici 1, Giuseppe Novelli 1, Sergio Bernardini 1

1 University 2 CASPUR

* Address correspondence to: E-mail: ales_valentini{at}yahoo.it

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 CaP therapies. Actually new approaches on treating advanced prostate cancer are focused on modulators of epigenetic transcriptional regulation. 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 PSA, and a down-regulation of AR 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, while 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 UGTs 2B15 and 2B17 towards active androgens and we did not found any modulation in gene expression of these enzymes it can be hypothesised that VPA might enhance DHT catabolism in this in vitro model and induces NE differentiation. Our data seem to be concerning CaP treatment with VPA.


Key words: cDNA arrays, UDP glucuronyltransferases


This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
D. E. Frigo and D. P. McDonnell
Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation
Mol. Cancer Ther., March 1, 2008; 7(3): 659 - 669.
[Abstract] [Full Text] [PDF]


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