Attenuation of cell cycle progression by 2,3,7,8-tetrachlorodibenzo-p-dioxin eliciting ovulatory blockade in gonadotropin-primed immature rats

Jung, Nak-Kyun; Park, Jy-Young; Park, Jeong-Hoh; Kim, Sun-Gyun; Park, Jin-Ki; Chang, Won-Kyong; Lee, Hwi-Cheul; Kim, Sung Woo; Chun, Sang-Young

doi:10.1507/endocrj.k10e-220

Cited by 18 publications

(9 citation statements)

References 38 publications

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“…A study on the ovulation rate in rats following TCDD exposure revealed that AhR ligand activation induces a G2/M cell cycle block resulting in a decrease in S-phase cells. This study also found that TCDD inhibits levels of Cdk2 and cyclin D2 [43]. The inhibitory effect has been seen with both genotoxic and non-gentoxic ligands for AhR.…”

Section: Discussionsupporting

confidence: 63%

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: Discussionsupporting

confidence: 63%

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

et al. 2014

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“…In vitro studies revealed there are two binding sites for Rb within two distinct AhR domains and that association only occurs after AhR activation and translocation to the nucleus [61]. Also, TCDD has been shown to decrease levels of cyclin D to block cell cycle progression as well as interrupt the direct interaction between AhR and CKD4 [62]. Disruption of CDK4 interaction results in decreased phosphorylation of Rb and G1 cell cycle arrest [63].…”

Section: Discussionmentioning

confidence: 99%

“…The protein interactions range from transcription factors to coactivator and corepressor proteins. Reported interactions include, NFkB, COUP-TF1 and TFIIB [62–64,68–70]. AhR and androgen receptor share a number of coactivator proteins such as SRC1 and p300 [71,72].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen independent signaling and growth in (C4-2) prostate cancer cells

Tran¹,

Richmond²,

Aaron³

et al. 2013

Biochemical Pharmacology

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The aryl hydrocarbon receptor is a member of the basic-helix-loop-helix family of transcription factors. AhR mediates the biochemical and toxic effects of a number of polyaromatic hydrocarbons such as 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD). AhR is widely known for regulating the transcription of drug metabolizing enzymes involved in the xenobiotic metabolism of carcinogens and therapeutic agents, such as cytochrome P450-1B1 (CYP1B1). Additionally, AhR has also been reported to interact with multiple signaling pathways during prostate development. Here we investigate the effect of sustained AhR signaling on androgen receptor function in prostate cancer cells. Immunoblot analysis shows that AhR expression is increased in androgen independent (C4-2) prostate cancer cells when compared to androgen sensitive (LNCaP) cells. RT-PCR studies revealed constitutive AhR signaling in C4-2 cells without the ligand induced activation required in LNCaP cells. A reduction of AhR activity by short RNA mediated silencing in C4-2 cells reduced expression of both AhR and androgen responsive genes. The decrease in androgen responsive genes correlates to a decrease in phosphorylated androgen receptor and androgen receptor expression in the nucleus. Furthermore, the forced decrease in AhR expression resulted in a 50% decline in the growth rate of C4-2 cells. These data indicates that AhR is required to maintain hormone independent signaling and growth by the androgen receptor in C4-2 cells. Collectively, these data provide evidence of a direct role for AhR in androgen independent signaling and provides insight into the molecular mechanisms responsible for sustained androgen receptor signaling in hormone refractory prostate cancer.

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“…Chromatin immunoprecipitation combined with microarrays (ChIP-chip) and gene expression microarray experiments revealed that AHR regulates numerous genes involved in diverse cellular pathways, including metabolism and cellcycle regulation (8)(9)(10). In support of these findings, previous studies have shown that TCDD inhibits cell proliferation (11)(12)(13).…”

Section: Introductionmentioning

confidence: 72%

FOXA1 Is Essential for Aryl Hydrocarbon Receptor–Dependent Regulation of Cyclin G2

Ahmed

Al-Saigh

Matthews

2012

Molecular Cancer Research

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recently, AHR has emerged as a potential therapeutic target for breast cancer by virtue of its ability to modulate estrogen receptor-a (ERa) signalling and/or its ability to block cell proliferation. Our previous studies identified cyclin G2 (CCNG2), an inhibitor of cellcycle progression, as an AHR target gene; however, the mechanism of this regulation is unknown. Chromatin immunoprecipitation assays in T-47D human breast cancer cells revealed a TCDD-dependent recruitment of AHR, nuclear co-activator 3 (NCoA3) and the transcription factor forkhead box A1 (FOXA1), a key regulator of breast cancer cell signaling, to CCNG2 resulting in increases in CCNG2 mRNA and protein levels. Mutation of the AHR response element (AHRE) and forkhead-binding sites abolished TCDD-induced CCNG2-regulated reporter gene activity. RNA interference-mediated knockdown of FOXA1 prevented the TCDD-dependent recruitment of AHR and NCoA3 to CCNG2 and reduced CCNG2 mRNA levels. Interestingly, knockdown of FOXA1 also caused a marked decrease in ERa, but not AHR protein levels. However, RNA interference-mediated knockdown of ERa, a negative regulator of CCNG2, had no effect on TCDD-dependent AHR or NCoA3 recruitment to or expression of CCNG2. These findings show that FOXA1, but not ERa, is essential for AHR-dependent regulation of CCNG2, assigning a role for FOXA1 in AHR action. Mol Cancer Res; 10(5); 636-48. Ó2012 AACR.

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Attenuation of cell cycle progression by 2,3,7,8-tetrachlorodibenzo-p-dioxin eliciting ovulatory blockade in gonadotropin-primed immature rats

Cited by 18 publications

References 38 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

Inhibition of constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen independent signaling and growth in (C4-2) prostate cancer cells

FOXA1 Is Essential for Aryl Hydrocarbon Receptor–Dependent Regulation of Cyclin G2

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