Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation

Morrow, Derek; Qin, Chunhua; Smith, Roger; Safe, Stephen

doi:10.1016/j.jsbmb.2003.10.005

Cited by 72 publications

(45 citation statements)

References 56 publications

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“…In addition, chemoprotective natural products including flavonoids, indole-3-carbinol and related heteroaromatics, green tea components, and other polyhydroxy aromatic antioxidants also bind the AhR (Denison, Seidel, Rogers, Ziccardi, Winter, and Heath-Pagliuso, 1998;Denison and Nagy, 2003) and exhibit both AhR agonist and antagonist activities. Ligand-dependent activation of the AhR inhibits growth of ERpositive breast cancer cells , and growth inhibitory effects of AhR agonists have also been observed in pancreatic, prostate and ovarian cancer (Koliopanus et al, 2002;Morrow et al, 2004;Rowlands et al, 1993). These observations have led to development of selective AhR modulators (SAhRMs) as a potential new class of drugs for treatment of these cancers (McDougal, Wormke, Calvin, and Safe, 2001;Safe, McDougal, Gupta, and Ramamoorthy, 2001;Safe and Wormke, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Khan

Liu

Stoner

et al. 2007

Toxicology and Applied Pharmacology

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The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and mRNA levels and also activates inhibitory AhR-Erα crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AhR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1α or other factors that sequester the AhR nuclear translocation (Arnt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NFκB which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 hr, BRCA1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 hr, BRCA1 was not decreased, but induction of CYP1A1 by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 hr enhanced CYP1A1 expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ahresponsiveness (under normoxia) that are also inhibited by cycloheximide.

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Section: Discussionmentioning

confidence: 99%

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Khan

Liu

Stoner

et al. 2007

Toxicology and Applied Pharmacology

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“…For example, p300 and CBP serve as coactivators for many different DNA-binding transcriptional activator proteins, and limiting amounts of p300 and CBP have been proposed as a possible explanation for mutual antagonistic effects between different transcriptional activators that require these coactivators (48). Similarly, the antagonistic effect of the ligand-activated aryl hydrocarbon receptor on transcriptional activation by AR (49,50) and the mutually antagonistic effects of activated AR and TCF/LEF on each other (9, 51, 52) might be due to competition for limiting cofactors, such as CoCoA, which are involved in transcriptional activation of both members of these antagonistic pairs of transcription factors. Thus, the involvement of CoCoA, ␤-catenin, GRIP1, and CARM1 in multiple transcriptional regulatory pathways (e.g.…”

Section: Discussionmentioning

confidence: 99%

Differential Use of Functional Domains by Coiled-coil Coactivator in Its Synergistic Coactivator Function with β-Catenin or GRIP1

Yang

Kim

et al. 2006

Journal of Biological Chemistry

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␤-Catenin, a pivotal component of the Wnt-signaling pathway, binds to and serves as a transcriptional coactivator for the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcriptional activator proteins and for the androgen receptor (AR), a nuclear receptor. Three components of the p160 nuclear receptor coactivator complex, including CARM1, p300/CBP, and GRIP1 (one of the p160 coactivators), bind to and cooperate with ␤-catenin to enhance transcriptional activation by TCF/LEF and AR. Here we report that another component of the p160 nuclear receptor coactivator complex, the coiled-coil coactivator (CoCoA), directly binds to and cooperates synergistically with ␤-catenin as a coactivator for AR and TCF/LEF. CoCoA uses different domains to bind GRIP1 and ␤-catenin, and it uses different domains to transmit the activating signal to the transcription machinery, depending on whether it is bound to GRIP1 or ␤-catenin. The Wnt/␤-catenin-signaling cascade plays important roles in developmental processes. Inappropriate activation of this pathway is associated with a variety of cancers such as colorectal cancer and hepatocellular carcinoma (1, 2). Activation of this pathway by extracellular Wnt ligands results in increased intracellular levels of ␤-catenin, which consists of N-and C-terminal activation domains flanking twelve armadillo repeats and serves as a coactivator for various DNA-binding transcription factors. In the absence of stimulation by Wnt ligand, ␤-catenin levels are maintained at a low level through a specific degradation mechanism. Phosphorylation of ␤-catenin by glycogen synthase kinase 3␤ targets ␤-catenin for ubiquitylation and degradation via ubiquitin-mediated proteasomal degradation (2, 3). Activation of the cell-surface Frizzled receptor by binding of the Wnt ligand activates a signaling pathway, which leads to inactivation of glycogen synthase kinase 3␤ by destabilizing its complex with axin and the adenomatous polyposis coli tumor suppressor protein. The resulting reduced degradation of ␤-catenin leads to enhanced cellular levels of ␤-catenin, which allows its nuclear translocation and accumulation. In the nucleus ␤-catenin binds to and serves as a primary coactivator for the T-cell factor/lymphoid enhancer factor (TCF/LEF) 3 proteins (4, 5). In so doing, ␤-catenin displaces the corepressors Groucho (6) and CtBP (7) and thus converts the TCF/LEF complex from a transcriptional repressor to a transcriptional activator.␤-Catenin also serves as a coactivator for the androgen receptor (AR) (8, 9), which is a member of the nuclear receptor (NR) family of hormone-regulated transcriptional activator proteins. Binding of hormone to AR results in a conformational change that allows AR to associate with specific target genes, either by direct binding of specific enhancer elements or through protein-protein interactions with other DNAbound transcription factors (10, 11). AR recruits a variety of coregulator proteins to the target gene promoter, and these coregulators mediate the activation or rep...

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“…AhR null mice are protected from TCDD-mediated tissue damage and teratogenicity (Fernandez-Salguero et al, 1996;Mimura et al, 1997) and BAPdependent tumor formation (Shimizu et al, 2000). Nevertheless, some say AhR ligands and selective AhR modulators are potential breast and prostate cancer therapies (Safe et al, 2000;Safe and McDougal, 2002;Loaiza-Perez et al, 2004;Morrow et al, 2004). Thus, relevance of AhR activation to toxicity is system-dependent.…”

Section: Discussionmentioning

confidence: 99%

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison With Classical Aryl Hydrocarbon Receptor Ligands and Atypical Cyp1a Inducers

Coe

Nelson

Ulrich³

et al. 2006

Drug Metab Dispos

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ABSTRACT:The antiandrogen flutamide (FLU) is used primarily for prostate cancer and is an idiosyncratic hepatotoxicant that sometimes causes severe liver problems. To investigate FLU's overt hepatic effects, especially on inducible drug clearance-related gene networks, FLU's hepatic gene expression profile was examined in female Sprague-Dawley rats using ϳ22,500 oligonucleotide microarrays. Rats were dosed daily for 3 days with FLU at 500, 250, 62.5, 31.3, and 15.6 mg/kg/day, and hepatic RNA was isolated. FLU resulted in the dose-dependent regulation of ϳ350 genes. Employing a gene-response compendium, FLU was compared with three classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene, benzo[a]pyrene, and ␤-naphthoflavone, and four atypical CYP1A inducers, indole-3-carbinol (I3C), omeprazole (OME), chlorpromazine (CPZ), and clotrimazole (CLO). The FLU gene response was comparable with classical AhR ligands across a signature AhR ligand gene set that included CYP1A1 and other members of the AhR gene battery. Dose-related responses of CYP1 genes established a maximum response ceiling and discerned potency differences in atypical inducers. FLU had a sharp down-regulation of c-fos that was comparable with all the compounds except CPZ and CLO. FLU absorption, distribution, metabolism, and excretion (ADME) gene expression analysis revealed that FLU, as well as I3C and OME, induced CYP2B and CYP3A, distinguishing them from the classical AhR ligands. By using a compendium of gene expression profiles, FLU was shown to signal in rats similar to an AhR activator with additional CYP2B and CYP3A effects that most resembled the ADME gene expression pattern of the atypical CYP1A inducers I3C and OME.

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Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation

Cited by 72 publications

References 56 publications

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Differential Use of Functional Domains by Coiled-coil Coactivator in Its Synergistic Coactivator Function with β-Catenin or GRIP1

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison With Classical Aryl Hydrocarbon Receptor Ligands and Atypical Cyp1a Inducers

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