The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells.

Moss PE, Lyles BE, Stewart LV
Exp Cell Res. 2010 316 (20): 3478-88

PMID: 20932825 · PMCID: PMC2977976 · DOI:10.1016/j.yexcr.2010.09.015

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Copyright © 2010 Elsevier Inc. All rights reserved.

MeSH Terms (20)

Androgen-Binding Protein Cell Line, Tumor Cell Proliferation Cyclin D1 Dihydrotestosterone Gene Expression Genes, Reporter Humans Hypoglycemic Agents Male Mutation Neoplasms, Hormone-Dependent PPAR gamma Prostate-Specific Antigen Prostatic Neoplasms Receptors, Androgen RNA, Small Interfering Rosiglitazone Thiazolidinediones Transfection

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