TY - JOUR
T1 - Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation
AU - Morrow, Derek
AU - Qin, Chunhua
AU - Smith, Roger
AU - Safe, Stephen
N1 - Funding Information:
In summary, results of this study demonstrate that TCDD and the SAhRM 6-MCDF inhibit growth of LNCaP prostate cancer cells and inhibit hormone-induced upregulation of AR protein. In contrast to AhR-dependent downregulation of ERα in breast cancer cells, AhR agonists alone did not affect AR levels in LNCaP cells and inhibitory AhR-AR crosstalk in transactivation experiments was promoter-dependent. These results suggest that ligand-dependent interactions between the AhR and AR signaling pathways are complex and current studies are investigating which key growth regulatory genes in LNCaP cells are targeted by the AhR. (Supported by Department of the Army DAMD17–02–1–0147).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/1
Y1 - 2004/1
N2 - LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and an Ah-responsive reporter gene. Similar results were obtained with the selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however, TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR) crosstalk was investigated in cells transfected with constructs containing the androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the -244 to -96 region of this promoter (pARR3). Ten nanomolar dihydrotestosterone (DHT) and 17β-estradiol (E2) induced transactivation in LNCaP cells transfected with pPB or pARR3; however, inhibitory AhR-AR crosstalk was observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or E2-induced transactivation in ZR-75 human breast cancer cells, indicating that these interactions were promoter and cell context-dependent. Both E2 and DHT stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF decreased AR protein levels. These results indicate that inhibitory AhR-AR crosstalk in prostate cancer cells is complex and for some responses, AR protein stability may play a role.
AB - LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and an Ah-responsive reporter gene. Similar results were obtained with the selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however, TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR) crosstalk was investigated in cells transfected with constructs containing the androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the -244 to -96 region of this promoter (pARR3). Ten nanomolar dihydrotestosterone (DHT) and 17β-estradiol (E2) induced transactivation in LNCaP cells transfected with pPB or pARR3; however, inhibitory AhR-AR crosstalk was observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or E2-induced transactivation in ZR-75 human breast cancer cells, indicating that these interactions were promoter and cell context-dependent. Both E2 and DHT stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF decreased AR protein levels. These results indicate that inhibitory AhR-AR crosstalk in prostate cancer cells is complex and for some responses, AR protein stability may play a role.
KW - Ah receptor
KW - Androgen receptor
KW - Inhibitory crosstalk
KW - LNCaP cells
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U2 - 10.1016/j.jsbmb.2003.10.005
DO - 10.1016/j.jsbmb.2003.10.005
M3 - Article
C2 - 15026081
AN - SCOPUS:1542269170
VL - 88
SP - 27
EP - 36
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
IS - 1
ER -