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.

Valentini, A., Biancolella, M., Amati, F., Gravina, P., Miano, R., Chillemi, G., et al. (2007). Valproic acid induces neuroendocrine differentiation and UGT2B7 up-regulation in human prostate carcinoma cell line. DRUG METABOLISM AND DISPOSITION, 35(6), 968-972 [10.1124/dmd.107.014662].

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

BIANCOLELLA, MICHELA;AMATI, FRANCESCA;MIANO, ROBERTO;Farcomeni, A;VESPASIANI, GIUSEPPE;DESIDERI, ALESSANDRO;FEDERICI, GIORGIO;NOVELLI, GIUSEPPE;BERNARDINI, SERGIO
2007-01-01

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.
2007
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/03 - GENETICA MEDICA
English
Con Impact Factor ISI
androgen receptor; androstanolone; glucuronosyltransferase 2b11; glucuronosyltransferase 2B7; histone deacetylase inhibitor; neuron specific enolase; prostate specific antigen; valproic acid; article; cancer growth; carcinoma cell; cell differentiation; cell strain LNCaP; controlled study; down regulation; drug effect; gene expression; growth inhibition; human; human cell; neuroendocrine system; priority journal; prostate carcinoma; protein degradation; protein expression; upregulation; Cell Differentiation; Cell Line, Tumor; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glucuronosyltransferase; Histone Deacetylases; Humans; Male; Neurosecretory Systems; Oligonucleotide Array Sequence Analysis; Phosphopyruvate Hydratase; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Up-Regulation; Valproic Acid
Valentini, A., Biancolella, M., Amati, F., Gravina, P., Miano, R., Chillemi, G., et al. (2007). Valproic acid induces neuroendocrine differentiation and UGT2B7 up-regulation in human prostate carcinoma cell line. DRUG METABOLISM AND DISPOSITION, 35(6), 968-972 [10.1124/dmd.107.014662].
Valentini, A; Biancolella, M; Amati, F; Gravina, P; Miano, R; Chillemi, G; Farcomeni, A; Bueno, S; Vespasiani, G; Desideri, A; Federici, G; Novelli, G; Bernardini, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/36546
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