Activation of Genes by Nuclear Receptor/Specificity Protein (Sp) Interactions in Cancer.

The human nuclear receptor (NR) superfamily consists of 48 genes that are ligand-activated transcription factors that play a key role in maintaining cellular homeostasis and in pathophysiology. NRs are important drug targets for both cancer and non-cancer endpoints as ligands for these receptors can act as agonists, antagonists or inverse agonists to modulate gene expression. With two exceptions, the classical mechanism of action of NRs involves their interactions as monomers, dimers or heterodimers with their cognate response elements (cis-elements) in target gene promoters.

1,4-dihydroxy-2-naphthoic acid prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor function deficits.

Parkinson's disease (PD), characterized by death of dopaminergic neurons in the substantia nigra, is the second most prevalent progressive neurodegenerative disease. However, the etiology of PD is largely elusive. This study employed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model to examine the effectiveness of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA), an aryl hydrocarbon receptor (AhR) active gut bacteria-derived metabolite, in mitigating MPTP's motoric deficits, and the role of AhR in mediating these effects.

Involvement of Intestinal Epithelium Aryl Hydrocarbon Receptor Expression and 3, 3'-Diindolylmethane in Colonic Tertiary Lymphoid Tissue Formation.

Tertiary lymphoid tissues (TLTs) are adaptive immune structures that develop during chronic inflammation and may worsen or lessen disease outcomes in a context-specific manner. Immune cell activity governing TLT formation in the intestines is dependent on immune cell aryl hydrocarbon receptor (AhR) activation. Homeostatic immune cell activity in the intestines is further dependent on ligand activation of AhR in intestinal epithelial cells (IECs), yet whether AhR activation and signaling in IECs influences the formation of TLTs in the presence of dietary AhR ligands is not known.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype.

The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity.

Comparative safety, pharmacokinetics, and off-target assessment of 1,1-bis(3'-indolyl)-1-(-chlorophenyl) methane in mouse and dog: implications for therapeutic development.

The modified phytochemical derivative, 1,1-bis(3'-indolyl)-1-(-chlorophenyl) methane (C-DIM12), has been identified as a potential therapeutic platform based on its capacity to improve disease outcomes in models of neurodegeneration and cancer. However, comprehensive safety studies investigating pathology and off-target binding have not been conducted. To address this, we administered C-DIM12 orogastrically to outbred male CD-1 mice for 7 days (50 mg/kg/day, 200 mg/kg/day, and 300 mg/kg/day) and investigated changes in hematology, clinical chemistry, and whole-body tissue pathology.

Aryl hydrocarbon receptor activity in intestinal epithelial cells in the formation of colonic tertiary lymphoid tissues.

After birth, the development of secondary lymphoid tissues (SLTs) in the colon is dependent on the expression of the aryl hydrocarbon receptor (AhR) in immune cells as a response to the availability of AhR ligands. However, little is known about how AhR activity from intestinal epithelial cells (IECs) may influence the development of tertiary lymphoid tissues (TLTs). As organized structures that develop at sites of inflammation or infection during adulthood, TLTs serve as localized centers of adaptive immune responses, and their presence has been associated with the resolution of inflammation and tumorigenesis in the colon.

Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands.

Bis-indole derived compounds such as 1,1-bis(3'-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC < 1 mg/kg/day), coupled with the >60% similarity of the ligand-binding domains (LBDs) of NR4A1 and NR4A2 and the pro-oncogenic activities of both receptors lead us to hypothesize that these compounds may act as dual NR4A1 and NR4A2 ligands. Using a fluorescence binding assay, it was shown that 22 synthetic DIM8-3,5 and DIM-3,5 analogs bound the LBD of NR4A1 and NR4A2 with most K values in the low µM range.

Natural products and synthetic analogs as selective orphan nuclear receptor 4A (NR4A) modulators.

Although endogenous ligands for the orphan nuclear receptor 4A1 (NR4A1, Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1) have not been identified, several natural products and synthetic analogs bind NR4A members. These studies are becoming increasingly important since members of the NR4A subfamily of 3 receptors are potential drug targets for treating cancer and non-cancer endpoints and particularly those conditions associated with inflammatory diseases. Ligands that bind NR4A1, NR4A2, and NR4A3 including Cytosporone B, celastrol, bis-indole derived (CDIM) compounds, tryptophan/indolic, metabolites, prostaglandins, resveratrol, piperlongumine, fatty acids, flavonoids, alkaloids, peptides, and drug families including statins and antimalarial drugs.

Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion.

There is evidence that the orphan nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in exhausted CD8 + T cells and regulates PD-L1 in tumors. This study investigated the effects of potent bis-indole-derived NR4A1 antagonists on reversing T-cell exhaustion and downregulating PD-L1 in colon tumors/cells. NR4A1 antagonists inhibited colon tumor growth and downregulated expression of PD-L1 in mouse colon MC-38-derived tumors and cells.

Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1).

Piperlongumine and derivatives are being developed as anticancer agents which act primarily as inducers of reactive oxygen species (ROS) in cancer cell lines. Many of the anticancer activities of piperlongumine resemble those observed for bis-indole derived compounds that bind the orphan nuclear receptor 4A1 (NR4A1) and act as inverse receptor agonists to inhibit NR4A1-regulated pro-oncogenic pathways and genes. In this study we show that like other NR4A1 inverse agonists piperlongumine inhibited RKO, SW480 and HCT116 colon cancer cell growth migration and invasion and induced apoptosis.

Flavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice.

Nuclear receptor 4A1 (NR4A1) plays an important role in endometriosis progression; levels of NR4A1 in endometriotic lesions are higher than in normal endometrium, and substituted bis-indole analogs (NR4A1) antagonists suppress endometriosis progression in mice with endometriosis. In addition, the flavonoids kaempferol and quercetin are natural products that directly bind NR4A1 and significantly repress the intrinsic NR4A1-dependent transcriptional activity in human endometriotic epithelial and stromal cells and Ishikawa endometrial cancer cells. NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin suppressed proliferation of human endometriotic epithelial cells and Ishikawa cells by inhibiting epidermal growth factor receptor/c-Myc/survivin-mediated growth-promoting and survival pathways, The mammalian target of rapamycin (mTOR) signaling and αSMA/CTGF/COL1A1/FN-mediated fibrosis signaling but increasing Thioredoxin domain Containing 5/SESN2-mediated oxidative/estrogen receptors stress signaling.

Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.

Unlabelled: Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-β1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-β1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice.

Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1).

It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this study, we investigated the interactions of flavone, six hydroxyflavones, seven dihydroxyflavones, three trihydroxyflavones, two tetrahydroxyflavones, and one pentahydroxyflavone with the ligand-binding domain (LBD) of NR4A1 using direct-binding fluorescence and an isothermal titration calorimetry (ITC) assays. Flavone and the hydroxyflavones bound NR4A1, and their K values ranged from 0.

Selective aryl hydrocarbon receptor modulators can act as antidepressants in obese female mice.

Background: Obese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice.

Methods: Obesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9-10 weeks.

Specificity Proteins (Sp) and Cancer.

The specificity protein (Sp) transcription factors (TFs) Sp1, Sp2, Sp3 and Sp4 exhibit structural and functional similarities in cancer cells and extensive studies of Sp1 show that it is a negative prognostic factor for patients with multiple tumor types. In this review, the role of Sp1, Sp3 and Sp4 in the development of cancer and their regulation of pro-oncogenic factors and pathways is reviewed. In addition, interactions with non-coding RNAs and the development of agents that target Sp transcription factors are also discussed.

Aryl Hydrocarbon Receptor (AhR) Signaling in Colonic Cells and Tumors.

The aryl hydrocarbon receptor (AhR) is overexpressed in many tumor types and exhibits tumor-specific tumor promoter and tumor suppressor-like activity. In colon cancer, most but not all studies suggest that the AhR exhibits tumor suppressor activity which is enhanced by AhR ligands acting as agonists. Our studies investigated the role of the AhR in colon tumorigenesis using wild-type and AhR-knockout mice, the inflammation model of colon tumorigenesis using mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS) and APC; Kras mice all of which form intestinal tumors.

Health Benefits of Coffee Consumption for Cancer and Other Diseases and Mechanisms of Action.

Coffee is one of the most widely consumed beverages worldwide, and epidemiology studies associate higher coffee consumption with decreased rates of mortality and decreased rates of neurological and metabolic diseases, including Parkinson's disease and type 2 diabetes. In addition, there is also evidence that higher coffee consumption is associated with lower rates of colon and rectal cancer, as well as breast, endometrial, and other cancers, although for some of these cancers, the results are conflicting. These studies reflect the chemopreventive effects of coffee; there is also evidence that coffee consumption may be therapeutic for some forms of breast and colon cancer, and this needs to be further investigated.

Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms.

The aryl hydrocarbon receptor (AhR) is a key regulator in the microbiome-gut-brain axis, and AhR-active microbial metabolites modulate multiple neuronal responses. We recently demonstrated that 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (DHNA), two selective AhR modulators (SAhRMs), act as antidepressants in female mice. Thus, to examine the role of intestinal AhR in depression, anxiety, and spatial learning, this study employed transgenic mice in which the AhR was knockout only in the intestinal epithelium (AhRΔIEC).

The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer.

Breast cancer is a complex disease which is defined by numerous cellular and molecular markers that can be used to develop more targeted and successful therapies. The aryl hydrocarbon receptor (AhR) is overexpressed in many breast tumor sub-types, including estrogen receptor -positive (ER+) tumors; however, the prognostic value of the AhR for breast cancer patient survival is not consistent between studies. Moreover, the functional role of the AhR in various breast cancer cell lines is also variable and exhibits both tumor promoter- and tumor suppressor- like activity and the AhR is expressed in both ER-positive and ER-negative cells/tumors.

Sex-dependent differences in the stress mitigating and antidepressant effects of selective aryl hydrocarbon receptor modulators.

Background: Our recent study demonstrated that selective aryl hydrocarbon receptor modulators (SAhRMs), such as 1,4-dihydroxy-2-napthoic acid (DHNA) act as antidepressants in female mice. Given that some effects of certain SAhRMs are known to also be mediated via estrogen receptor signaling, this study examined whether the effects of SAhRMs on mood, emotional state, and cognition are sex-dependent.

Methods: C57BL/6N mice were fed with vehicle or 20 mg/kg DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS).

Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer.

Early stage estrogen receptor α (ERα, ESR1)-positive breast cancer patients can develop more aggressive endocrine-resistant tumors that express constitutively active mutant forms of ERα including ERα-Y537S and ERα-D538G. These patients are treated with selective ER down regulators (SERDs) such as the ERα antagonist fulvestrant. Previous studies show that histone deacetylase (HDAC) inhibitors downregulate ERα and since some dietary derived short chain fatty acids (butyrate, propionate and acetate) exhibit HDAC inhibitory activity we investigated their effects as SERDs in MCF-7 and T47D cells expressing wild-type and mutant ERα-D538G and ERα-Y537S.

Structure-activity relationships among mono- and dihydroxy flavones as aryl hydrocarbon receptor (AhR) agonists or antagonists in CACO2 cells.

Unsubstituted flavone induced CYP1A1, CYP1B1 and UGT1A1 gene expression in Caco2 cells and was characterized as an aryl hydrocarbon receptor (AhR) agonist. The structure-activity relationships among 15 mono- and dihydroxyflavones showed that addition of one or two hydroxyl groups resulted in active (e.g.