Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands

Hrubá, Eva; Vondráček, Jan; Líbalová, Helena; Topinka, Jan; Bryja, Vı́tězslav; Souček, Karel; Machala, Miroslav

doi:10.1016/j.toxlet.2011.07.011

Cited by 41 publications

(27 citation statements)

References 49 publications

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“…This idea is supported by gene microarray studies which have reported the ability of different AhR ligands to not only induce expression of a common set of gene products but to also induce a distinctly different, ligandspecific set of AhR-dependent gene products (21)(22)(23). Ligandspecific modulation of the AhR signaling pathway has been suggested to result from ligand-dependent changes in the AhR which could allow it to interact with different nuclear factors or dimerization partners, to bind to unconventional DREs or unique DNA sequences, and/or to be bound by different coactivators (24)(25)(26)(27).…”

mentioning

confidence: 87%

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

Soshilov

Denison

2014

Molecular and Cellular Biology

109

106

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by structurally diverse chemicals. To examine the mechanisms responsible for the promiscuity in AhR ligand binding, we determined the effects of mutations within the AhR ligand-binding domain (LBD) on the activity of diverse AhR ligands. Site-directed mutagenesis identified Ile319 of the mouse AhR and, to a lesser extent, Phe318 as residues involved in ligand-selective modulation of AhR transformation using a panel of 12 AhR ligands. These ligands could be categorized into four distinct structurally related groups based on their ability to activate AhR mutants at position 319 in vitro. The mutation I319K was selectively activated by FICZ and not by other examined ligands in vitro and in cell culture. F318L and F318A mutations resulted in the conversion of AhR agonists ␤-naphthoflavone and 3-methylcholanthrene, respectively, into partial agonists/antagonists. Hsp90 binding to the AhR was decreased with several mutations and was inversely correlated with AhR ligand-binding promiscuity. Together, these data define overlapping amino acid residues within the AhR LBD involved in the selectivity of ligand binding, the agonist or antagonist mode of ligand binding, and hsp90 binding and provide insights into the ligand diversity of AhR activators.

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mentioning

confidence: 87%

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

Soshilov

Denison

2014

Molecular and Cellular Biology

109

106

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“…Despite these initial successes, more gene therapy targets for prostate cancer are still needed. In this study, we investigated the role of one gene that has been previously associated with human prostate carcinoma cells-myelodysplasia/myeloid leukemia factor 1 interacting protein (MLF1IP; also known as centromere protein U (CENPU), Cenp-50/PBIP1, or KLIP1) [6,7]-in order to better ascertain its role in human prostate carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

MLF1 interacting protein: a potential gene therapy target for human prostate cancer?

Zhang

Shao

et al. 2015

Med Oncol

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Here, we investigated the role of one gene that has been previously associated with human prostate carcinoma cells-myelodysplasia/myeloid leukemia factor 1 interacting protein (MLF1IP)-in order to better ascertain its role in human prostate carcinogenesis. The prostate cancer cell line PC-3 was lentivirally transfected to silence endogenous MLF1IP gene expression, which was confirmed by real-time quantitative PCR (RT-qPCR). Cellomics ArrayScan VTI imaging and MTT assays were conducted to assess cell proliferation. Cell cycle phase arrest and apoptosis were assayed by flow cytometry. Colony formation was assessed by fluorescence microscopy. MLF1IP gene expression was also analyzed by RT-qPCR in sixteen prostate cancer tissue samples and six healthy control prostate tissue samples from human patients. Cell proliferation was significantly inhibited in MLF1IP-silenced cells relative to control cells. G1 phase, S and G2/M phase cell counts were not significantly changed in MLF1IP-silenced cells relative to control cells. Apoptosis was significantly increased in MLF1IP-silenced cells, while MLF1IP-silenced cells displayed a significantly reduced number of cell colonies, compared to control cells. The 16 human prostate cancer tissue samples revealed no clear upregulation or downregulation in MLF1IP gene expression. MLF1IP significantly promotes prostate cancer cell proliferation and colony formation and significantly inhibits apoptosis without affecting cell cycle phase arrest. Further study is required to conclusively determine whether MLF1IP is upregulated in human prostate cancer tumors and to determine the precise cellular mechanism(s) for MLF1IP in prostate carcinogenesis.

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“…One of the major group of EDCs are carcinogenic polycyclic aromatic hydrocarbons (PAHs) which are known as genotoxic agents and ligands of the AhR. AhR has been suggested to have an important role in prostate carcinogenesis (Hruba et al, 2011) and environmental and developmental exposure to EDCs especially PAHs with estrogenic activity induce estrogen reprogramming of the prostate gland and causes permanent alterations in structure and gene expression which may lead to an increased risk of prostate cancer with aging (Hu et al, 2012). EDCs act directly through interaction with estrogen receptors (ERs) or indirectly through activation of AhR or by modulation of critical metabolic enzymes engaged in estrogen biosynthesis and metabolism (Schmidt and Peterlin-Masic 2012).…”

Section: Discussionmentioning

confidence: 99%

Prostate-Specific Antigen Levels in Relation to Background Factors: Are there Links to Endocrine Disrupting Chemicals and AhR Expression?

Bidgoli

Jabari²,

Zavarhei³

2014

Asian Pacific Journal of Cancer Prevention

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Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands

Cited by 41 publications

References 49 publications

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

MLF1 interacting protein: a potential gene therapy target for human prostate cancer?

Prostate-Specific Antigen Levels in Relation to Background Factors: Are there Links to Endocrine Disrupting Chemicals and AhR Expression?

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