scholarly journals AhR and Cancer: From Gene Profiling to Targeted Therapy

2021 ◽  
Vol 22 (2) ◽  
pp. 752
Author(s):  
Anaïs Paris ◽  
Nina Tardif ◽  
Marie-Dominique Galibert ◽  
Sébastien Corre
Keyword(s):  
Biological Activities ◽  
Critical Role ◽  
Genomic Data ◽  
Gene Profiling ◽  
Data Sets ◽  
Tumor Cell Lines ◽  
Aryl Hydrocarbon ◽  
Vital Functions ◽  
Expression And Activity

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been shown to be an essential regulator of a broad spectrum of biological activities required for maintaining the body’s vital functions. AhR also plays a critical role in tumorigenesis. Its role in cancer is complex, encompassing both pro- and anti-tumorigenic activities. Its level of expression and activity are specific to each tumor and patient, increasing the difficulty of understanding the activating or inhibiting roles of AhR ligands. We explored the role of AhR in tumor cell lines and patients using genomic data sets and discuss the extent to which AhR can be considered as a therapeutic target.

scholarly journals AhR and Cancer: from Gene Profiling to Targeted Therapy

2020 ◽  
Author(s):  
Anaïs PARIS ◽  
Nina TARDIF ◽  
Marie-Dominique GALIBERT ◽  
Sébastien CORRE
Keyword(s):  
Biological Activities ◽  
Critical Role ◽  
Genomic Data ◽  
Gene Profiling ◽  
Data Sets ◽  
Tumor Cell Lines ◽  
Aryl Hydrocarbon ◽  
Vital Functions ◽  
Expression And Activity

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been shown to be an essential regulator of a broad spectrum of biological activities required for maintaining the body's vital functions. AhR also plays a critical role in tumorigenesis. Its role in cancer is complex, encompassing both pro- and anti-tumorigenic activities. Its level of expression and activity are specific to each tumor and patient, increasing the difficulty of understanding the activating or inhibiting roles of AhR ligands. We explored the role of AhR in tumor cell lines and patients using genomic data sets and discuss the extent to which AhR can be considered as a therapeutic target.

scholarly journals Aberrant ALOX5 Activation Correlates with HER2 Status and Mediates Breast Cancer Biological Activities through Multiple Mechanisms

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Xiao Zhou ◽  
Yi Jiang ◽  
Qiuyun Li ◽  
Zhen Huang ◽  
Huawei Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Biological Activities ◽  
Critical Role ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Mesenchymal Transition ◽  
And Migration ◽  
Expression And Activity

Arachidonate lipoxygenases (ALOX) have been implicated in playing a critical role in tumorigenesis, development, and metastasis. We previously reported that ALOX12 is involved in breast cancer chemoresistance. In this study, we demonstrate that the ALOX5 activation correlates with the HER2 expression and mediates breast cancer growth and migration. We found that the ALOX5 expression and activity were upregulated in breast cancer patients, particularly in those tissues with HER2-positive. ALOX5 upregulation was also observed in HER2-positive breast cancer cells. In contrast, HER2 inhibition led to decreased expression and activity of ALOX5 but not ALOX5AP, suggesting that HER2 specifically regulates the ALOX5 expression and activity in breast cancer cells. We further demonstrated that ALOX5 is important for breast cancer biological activities with the predominant roles in growth and migration, likely through RhoA, focal adhesion, and PI3K/Akt/mTOR signaling but not epithelial mesenchymal transition (EMT). Our work is the first to report a correlation between the ALOX5 activity and HER2 overexpression in breast cancer. Our findings also highlight the therapeutic value of inhibiting ALOX5 in breast cancer, particularly those patients with the HER2 overexpression.

scholarly journals 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

2012 ◽  
Vol 113 (9) ◽  
pp. 1343-1352 ◽  
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Arterial ◽  
Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

scholarly journals AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner

2020 ◽  
Vol 21 (24) ◽  
pp. 9613
Author(s):  
Wurood Hantoosh Neamah ◽  
Philip Brandon Busbee ◽  
Hasan Alghetaa ◽  
Osama A. Abdulla ◽  
Mitzi Nagarkatti ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Critical Role ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Dependent Manner ◽  
Myeloid Derived Suppressor Cells ◽  
Aryl Hydrocarbon ◽  
Cxc Chemokine ◽  
Consequent Effect

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.

The Role of Chirality in the Activity of Photosystem II Herbicides

1987 ◽  
Vol 42 (6) ◽  
pp. 663-669 ◽  
Author(s):  
Gary Gardner ◽  
James R. Sanborn
Keyword(s):  
Photosystem Ii ◽  
Biological Activities ◽  
Critical Role ◽  
Optically Active ◽  
Chiral Discrimination ◽  
In Vitro Assays ◽  
Optical Isomers ◽  
Steric Factors

Although significant differences in activity between optical isomers have been recognized in many types of pesticides, the role of stereoselectivity has not been fully characterized for one of the most important classes of commercial herbicides, those that inhibit photosynthetic electron transport. This report describes experiments in which optically active α-methylbenzylamine or sec-butylamine was used as starting material for the synthesis of optically active triazine and urea herbicides. The biological activities of the compounds were determined in two in vitro chloroplast assays - competition for specifically bound [14C]atrazine and inhibition of photosystem II-medi- ated dye reduction - as well as in whole plant phytotoxicity. In both in vitro assays the (-)-isomer of the N-a-methylbenzyl triazine was about 15-fold more active than the (+)-isomer, and the racemate fell in between and was of about the same potency as atrazine. The same relative activities were also seen for in vivo phytotoxicity. The a-methylbenzyl urea derivatives were much less herbicidally active, but the in vitro assays were able to discriminate between the optical isomers. In both assays, the (-)-isomer of the urea was much more active than the (+)-isomer, with the racemate intermediate. Steric factors play a critical role in the degree of this chiral discrimination, since in both the corresponding triazines and ureas, the optically active molecules synthesized from the enantiomers of 2-butylamine showed only slight differences in activity. Saturation of the phenyl ring of the a-methylbenzyl triazines resulted in molecules which still showed substantial differences in activity related to chirality, further supporting the importance of steric factors, rather than electronic, in this chiral discrimination.

scholarly journals Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

2020 ◽  
Vol 21 (10) ◽  
pp. 3486 ◽  
Author(s):  
Wen-Chih Liu ◽  
Jia-Fwu Shyu ◽  
Paik Seong Lim ◽  
Te-Chao Fang ◽  
Chien-Lin Lu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Indoxyl Sulfate ◽  
Raw 264.7 Cells ◽  
High Dose ◽  
Activated T Cells ◽  
Aryl Hydrocarbon

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

scholarly journals A40 INTESTINAL EPITHELIAL NCOR1 TARGETS TRYPTOPHAN METABOLISM AND PROTECTS AGAINST EXPERIMENTAL COLITIS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 48-49
Author(s):  
M Lecours ◽  
A Di Castro ◽  
V Reyes-Nicolas ◽  
S St-Jean ◽  
A Loiselle ◽  
...  
Keyword(s):  
Target Genes ◽  
Gastrointestinal Disease ◽  
Critical Role ◽  
Experimental Colitis ◽  
Tryptophan Metabolism ◽  
Gene Profiling ◽  
Intestinal Epithelial ◽  
Tryptophan Degradation ◽  
And Control

Abstract Background The nuclear co-repressor NCOR1 is a central protein that orchestrates the assembly of a large transcriptional repression complex. NCOR1 controls activation of macrophages by repressing a large variety of pro-inflammatory genes. Aims We aimed to investigate the role of intestinal epithelial NCOR1 during experimental colitis. Methods Conditional deletion of Ncor1 in the whole intestinal epithelium was achieved by crossing Villin-Cre and Ncor1loxP/loxP C57BL/6 mouse models. A gene profiling analysis in the colon of non-diseased NCOR1ΔIEC and control mice was performed. NCOR1ΔIEC and control littermate mice were treated with dextran sulfate sodium (DSS) in drinking water. Results DSS-induced colitis in NCOR1ΔIEC mice was more severe than control mice according to survival as well as clinical observations. A statistical analysis predicted 85 unique and mapped transcripts being significantly modulated between NCOR1ΔIEC and control mice. An Ingenuity Pathway Analysis from these predicted target genes identified gastrointestinal disease (79 transcripts) as top disease and biofunction. Analysis of enriched targets in specific canonical pathways predicted an increase in the tryptophan degradation pathway (P = 3.2E-02), a pathway recently demonstrated to be strongly relevant to inflammatory bowel disease severity. Indoleamine-pyrrole 2,3-dioxygenase (IDO1), that catalyzes the first and rate-limiting step of tryptophan oxidation, was induced more than 7 times in the colon of NCOR1ΔIEC mice. Induction of Ido1 was also confirmed in cultured ex vivo colon organoids deleted for Ncor1. Conclusions Our results highlight the critical role of NCOR1 to maintain intestinal inflammatory homeostasis during experimental colitis and uncover a novel function for NCOR1 in the regulation of Ido1 expression and potentially tryptophan metabolism. Funding Agencies CIHR

scholarly journals Critical Role of Cys168 in Noggin Protein's Biological Function

2005 ◽  
Vol 37 (3) ◽  
pp. 181-185
Author(s):  
Wei-Dong Liu ◽  
Xiang-Ling Feng ◽  
Cai-Ping Ren ◽  
Jian-Ling Shi ◽  
Xu-Yu Yang ◽  
...  
Keyword(s):  
Biological Activities ◽  
Critical Role ◽  
Ectopic Expression ◽  
Disulfide Bridge ◽  
Site Directed Mutagenesis ◽  
Morphogenetic Protein ◽  
Neural Cell Adhesion ◽  
A Site ◽  
The Relationship

Abstract Previous that noggin exerts its neural inducing effect by binding and antagonizing bone morphogenetic protein 4 (BMP4). In order to further clarify the relationship between the structure and the function of noggin, and elucidate the possible mechanism responsible for noggin-BMP4 interaction, we generated three noggin mutants, C168S, C174S and C197S, by using a site-directed mutagenesis method. Ectopic expression of wild-type (WT) noggin, C174S or C197S, in Xenopus animal caps (ACs) by mRNA injection converted the explants (prospective ectoderm) into neural tissue, as indicated by the neural-like morphology and expression of the neural cell adhesion molecule (NCAM) in the ACs. In contrast, ACs expressing C168S suffered an epidermal fate similar to the control caps. Similarly, among the three mutants, only C168S lost the dorsalizing function. These studies highlight the critical role played by Cys168 in noggin's biological activities. It probably participates in the formation of an intermolecular disulfide bridge.

scholarly journals Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Michelle M Lissner ◽  
Katherine Cumnock ◽  
Nicole M Davis ◽  
José G Vilches-Moure ◽  
Priyanka Basak ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Metabolic Response ◽  
Acute Infection ◽  
Critical Role ◽  
Kidney Injury ◽  
High Plasma ◽  
Metabolic Reprogramming ◽  
Aryl Hydrocarbon ◽  
Specific Effects

Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.

scholarly journals VEGF Is Involved in the Increase of Dermal Microvascular Permeability Induced by Tryptase

2012 ◽  
Vol 2012 ◽  
pp. 1-8
Author(s):  
Qianming Bai ◽  
Xiaobo Li ◽  
Xinhong Wang ◽  
Yali Xu ◽  
Li Wang ◽  
...  
Keyword(s):  
Mast Cell ◽  
Vascular Permeability ◽  
Serine Proteases ◽  
Biological Activities ◽  
Critical Role ◽  
Rt Pcr ◽  
Protein Levels ◽  
Permeability Enhancement ◽  
Catalytic Inhibitor

Tryptases are predominantly mast cell-specific serine proteases with pleiotropic biological activities and play a critical role in skin allergic reactions, which are manifested with rapid edema and increases of vascular permeability. The exact mechanisms of mast cell tryptase promoting vascular permeability, however, are unclear and, therefore, we investigated the effect and mechanism of tryptase or human mast cells (HMC-1) supernatant on the permeability of human dermal microvascular endothelial cells (HDMECs). Both tryptase and HMC-1 supernatant increased permeability of HDMECs significantly, which was resisted by tryptase inhibitor APC366 and partially reversed by anti-VEGF antibody and SU5614 (catalytic inhibitor of VEGFR). Furthermore, addition of tryptase to HDMECs caused a significant increase of mRNA and protein levels of VEGF and its receptors (Flt-1 and Flk-1) by Real-time RT-PCR and Western blot, respectively. These results strongly suggest an important role of VEGF on the permeability enhancement induced by tryptase, which may lead to novel means of controlling allergic reaction in skin.

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