Repression of Activated Aryl Hydrocarbon Receptor–Induced Transcriptional Activation by 5α-Dihydrotestosterone in Human Prostate Cancer LNCaP and Human Breast Cancer T47D Cells

Sanada, Noriko; Gotoh, Yuka; Shimazawa, Rumiko; Klinge, Carolyn M.; Kizu, Ryoichi

doi:10.1254/jphs.08328fp

Cited by 36 publications

(23 citation statements)

References 35 publications

(29 reference statements)

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“…However, the inhibitory effect of DHT was abolished by knockdown of the androgen receptor protein with siRNA. It was determined that DHT induced heterodimerization between AR and AhR when cells were also treated with an AhR agonist [48]. The data presented here, reveals that AhR can modulate proliferation of prostate cancer cells in the absence of androgen receptor.…”

Section: Discussionmentioning

confidence: 57%

The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells

et al. 2014

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BackgroundDistant prostate cancers are commonly hormone refractory and exhibit increased growth no longer inhibited by androgen deprivation therapy. Understanding all molecular mechanisms contributing to uncontrolled growth is important to obtain effective treatment strategies for hormone refractory prostate cancers (HRPC). The aryl hydrocarbon receptor (AhR) affects a number of biological processes including cell growth and differentiation. Several studies have revealed that exogenous AhR ligands inhibit cellular proliferation but recent evidence suggests AhR may possess intrinsic functions that promote cellular proliferation in the absence of exogenous ligands.Methods/ResultsqRT-PCR and western blot analysis was used to determine AhR mRNA and protein expression in hormone sensitive LNCaP cells as well as hormone refractory DU145, PC3 and PC3M prostate cancer cell lines. LNCaP cells express AhR mRNA and protein at a much lower level than the hormone refractory cell models. Cellular fractionation and immunocytochemistry revealed nuclear localization of AhR in the established hormone refractory cell lines while LNCaP cells are devoid of nuclear AhR protein. qRT-PCR analysis used to assess basal CYP1B1 levels and a xenobiotic responsive element binding assay confirmed ligand independent transcriptional activity of AhR in DU145, PC3 and PC3M cells. Basal CYP1B1 levels were decreased by treatment with specific AhR inhibitor, CH223191. An in vitro growth assay revealed that CH223191 inhibited growth of DU145, PC3 and PC3M cells in an androgen depleted environment. Immunohistochemical staining of prostate cancer tissues revealed increased nuclear localization of AhR in grade 2 and grade 3 cancers compared to the well differentiated grade 1 cancers.ConclusionsTogether, these results show that AhR is constitutively active in advanced prostate cancer cell lines that model hormone refractory prostate cancer. Chemical ablation of AhR signaling can reduce the growth of advanced prostate cancer cells, an effect not achieved with androgen receptor inhibitors or growth in androgen depleted media.

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Section: Discussionmentioning

confidence: 57%

The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells

et al. 2014

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“…On the other hand, we could not find androgen receptor (AR)-binding element in the spacer region. Recently, it has been suggested that complex formation between activated AR and AhR plays an important role in suppression of the AhR-mediated transcription of CYP1 family genes (Sanada et al 2009). Therefore, the androgen-mediated down-regulation observed in this study is thought to occur, at least in part, through a complex formation between AR and AhR.…”

Section: Discussionmentioning

confidence: 99%

Androgen-mediated down-regulation of CYP1A subfamily genes in the pig liver

Kojima¹,

Sekimoto²,

Degawa³

2010

Journal of Endocrinology

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In Meishan and Landrace pigs, sex differences in the constitutive expression of hepatic cytochrome P4501A (CYP1A) subfamily enzymes were examined in terms of their mRNA, protein, and enzyme activity. All the results from the real-time RT-PCR, western blotting, and enzyme assays for CYP1A subfamily enzymes indicated that, in 5-month-old Meishan pigs, the expression levels of CYP1A1 and CYP1A2 in males were significantly low as compared with those in females. In contrast, there were no such significant sex differences in Landrace pigs. Castration of male Meishan pigs led to a female-type expression of the CYP1A subfamily enzymes, whereas no such effect was observed in male Landrace pigs after castration. In both breeds of pigs, the administration of testosterone propionate to the females and castrated males led to marked decreases in the expression levels of mRNAs and proteins in the CYP1A subfamily enzymes, and also in their enzyme activities. Furthermore, the correlation analyses between the serum testosterone level and the gene expression levels of CYP1A subfamily enzymes in different sex-matured (1-5-month-old) male pigs revealed that the clear decrease in expression levels of hepatic CYP1A subfamily enzymes occurred at concentrations of more than 33 ng/ml of serum testosterone. Incidentally, the mean concentrations of serum testosterone in 5-month-old Landrace and Meishan pigs were around 18 and 50 ng/ml respectively. In conclusion, we demonstrated for the first time that the serum testosterone level is one of the physiological factors which regulate constitutive expression of hepatic CYP1A1 and CYP1A2 in pigs.

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“…Additionally, inclusion of TCDD blocked androgen-dependent cell proliferation in cell culture [40]. A mechanism for the cross-talk was proposed where the androgen receptor and the AHR form a complex, altering transcription [41]. Further studies showed that activated AHR decreased the protein level of androgen receptor through an increase in targeted protein degradation through an E3 ubiquitin ligase complex in prostate cancer cells [42].…”

Section: Discussionmentioning

confidence: 99%

Isoform distinct time-, dose-, and castration-dependent alterations in flavin-containing monooxygenase expression in mouse liver after 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment

Novick

Vezina

Elfarra

2010

Biochemical Pharmacology

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Flavin-containing monooxygenase (FMO) expression in male mouse liver is altered after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or castration. Because TCDD is slowly eliminated from the body, we examined hepatic Fmo mRNA alterations for up to 32 days following 10 or 64 µg/kg TCDD exposure by oral gavage in male C57BL/6J mice. Fmo2 mRNA was significantly induced at 1, 4, and 8 days whereas Fmo3 mRNA was also induced at 32 days relative to controls. Fmo3 mRNA levels exhibited a dose-dependent increase at 4, 8, and 32 days after exposure; Fmo1, Fmo4, and Fmo5 mRNA did not exhibit clear trends. Because castration alone also increased Fmo2, Fmo3, and Fmo4 mRNA we examined the combined effects of castration and TCDD treatment on FMO expression. A greater than additive effect was observed with Fmo2 and Fmo3 mRNA expression. Fmo2 mRNA exhibited a 3–5 fold increase after castration or 10 µg/kg TCDD exposure by oral gavage, whereas an approximately 20-fold increase was observed between the sham-castrated control and castrated TCDD-treated mice. Similarly, treatment with 10 µg/kg TCDD alone increased Fmo3 mRNA 130- and 180-fold in the sham-castrated and castrated mice compared to their controls respectively, whereas, Fmo3 mRNA increased approximately 1900-fold between the sham control and castrated TCDD-treated mice. An increase in hepatic Fmo3 protein in TCDD treated mice was observed by immunoblotting and assaying methionine S-oxidase activity. Collectively, these results provide evidence for isoform distinct time-, dose-, and castration-dependent effects of TCDD on FMO expression and suggest cross-talk between TCDD and testosterone signal transduction pathways.

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Repression of Activated Aryl Hydrocarbon Receptor–Induced Transcriptional Activation by 5α-Dihydrotestosterone in Human Prostate Cancer LNCaP and Human Breast Cancer T47D Cells

Cited by 36 publications

References 35 publications

The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells

The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells

Androgen-mediated down-regulation of CYP1A subfamily genes in the pig liver

Isoform distinct time-, dose-, and castration-dependent alterations in flavin-containing monooxygenase expression in mouse liver after 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment

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