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Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma Through Nuclear Hormone Receptor Activation

ABSTRACT: Melanoma metastasis is a devastating outcome in need of novel preventive therapies. We provide pharmacologic, nolecuar, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Molecular and genetic experiments revealed these effects to be mediated by LXRb, which elicits these outcomes through transcriptional induction of tumoral and systemic apolipoprotein-E (ApoE). LXRb agonism robustly suppressed tumor growth and metastasis across a wide spectrum of melanoma lines of diverse mutational subtypes established in xenograft, immunocompetent, and genetically-initiated model. We propose a path for the clinical testing of LXRb targeting-a therapeutic approach that uniquely acts by transcriptionally acivating a metastasis suppressor gene. In this experiment we analyzed the effect of GW3965 treatment on gene expression in the MeWo human melanoma cell line. The cells were treated either with DMSO or GW3965 at 1 micromolar for 48 hours, after which the RNA was extracted and gene expression was analyzed by transcriptomic profiling

ORGANISM(S): Homo sapiens

SUBMITTER: Pencheva Nora

PROVIDER: S-ECPF-GEOD-48782 | biostudies-other |

REPOSITORIES: biostudies-other

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Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma Through Nuclear Hormone Receptor Activation

Project description:Melanoma metastasis is a devastating outcome in need of novel preventive therapies. We provide pharmacologic, nolecuar, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Molecular and genetic experiments revealed these effects to be mediated by LXRb, which elicits these outcomes through transcriptional induction of tumoral and systemic apolipoprotein-E (ApoE). LXRb agonism robustly suppressed tumor growth and metastasis across a wide spectrum of melanoma lines of diverse mutational subtypes established in xenograft, immunocompetent, and genetically-initiated model. We propose a path for the clinical testing of LXRb targeting-a therapeutic approach that uniquely acts by transcriptionally acivating a metastasis suppressor gene. In this experiment we analyzed the effect of GW3965 treatment on gene expression in the MeWo human melanoma cell line. The cells were treated either with DMSO or GW3965 at 1 micromolar for 48 hours, after which the RNA was extracted and gene expression was analyzed by transcriptomic profiling

2014-06-01 | E-GEOD-48782 | biostudies-arrayexpress

Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma Through Nuclear Hormone Receptor Activation

2014-06-01 | GSE48782 | GEO

PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation.

Project description:PI3K/AKT pathway activation is thought to be a driving force in metastatic melanomas. Members of the pleckstrin homology (PH) domain leucine-rich repeat protein Ser/Thr specific phosphatase family (PHLPP1 and PHLPP2) can regulate AKT activation. By dephosphorylating specific serine residues in the hydrophobic motif, PHLPP1 and PHLPP2 restrain AKT signalings, thereby regulating cell proliferation and survival. We here show that PHLPP1 expression was significantly downregulated or lost and correlated with metastatic potential in melanoma. Forcing expression of either PHLPP1 or PHLPP2 in melanoma cells inhibited cell proliferation, migration, and colony formation in soft agar; but PHLPP1 had the most profound inhibitory effect on metastasis. Moreover, expression of PH mutant forms of PHLPP1 continued to inhibit metastasis, whereas a phosphatase-dead C-terminal mutant did not. The introduction of activated PHLPP1-specific targets AKT2 or AKT3 also promoted melanoma metastasis, while the non-PHLPP1 target AKT1 did not. AKT2 and AKT3 could even rescue the PHLPP1-mediated inhibition of metastasis. An AKT inhibitor blocked the activity of AKT2 and inhibited AKT2-mediated tumor growth and metastasis in a preclinical mouse model. Our data demonstrate that PHLPP1 functions as a metastasis suppressor through its phosphatase activity, and suggest that PHLPP1 represents a novel diagnostic and therapeutic marker for metastatic melanoma.

| S-EPMC6450546 | biostudies-literature

Azithromycin: The First Broad-spectrum Therapeutic.

Project description:The Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services demarcates the need for drugs which target multiple types of pathogens to prepare for infectious threats. Azithromycin is one such broad-spectrum therapeutic that is both included in the University of Oxford's RECOVERY and excluded from the World Health Organization's SOLIDARITY trials. Here we review azithromycin's broad antibiotic, antimalarial, antiviral pharmacology and contextualise it against a broader history as the most disease-repositioned therapeutic of the macrolide class; we further evaluate azithromycin's clinical and socio-economic propriety for respiratory pandemics and delineate a model for its combinatorial mechanism of action against COVID-19 pneumonia.

| S-EPMC7439010 | biostudies-literature

Azithromycin: The First Broad-spectrum Therapeutic.

Project description:The Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services demarcates the need for drugs which target multiple types of pathogens to prepare for infectious threats. Azithromycin is one such broad-spectrum therapeutic that is both included in the University of Oxford's RECOVERY and excluded from the World Health Organization's SOLIDARITY trials. Here we review azithromycin's broad antibiotic, antimalarial, antiviral pharmacology and contextualise it against a broader history as the most repositioned therapeutic of the macrolide class; we further evaluate azithromycin's clinical and socio-economic propriety for respiratory pandemics and delineate a model for its combinatorial mechanism of action against COVID-19 pneumonia.

| S-EPMC7434625 | biostudies-literature

microRNA-22 promotes heart failure through coordinate suppression of PPAR/ERR-nuclear hormone receptor transcription.

Project description:Increasing evidence suggests that microRNAs are intimately involved in the pathophysiology of heart failure. MicroRNA-22 (miR-22) is a muscle-enriched miRNA required for optimum cardiac gene transcription and adaptation to hemodynamic stress by pressure overload in mice. Recent evidence also suggests that miR-22 induces hypertrophic growth and it is oftentimes upregulated in end stage heart failure. However the scope of mRNA targets and networks of miR-22 in the heart failure remained unclear. We analyzed transgenic mice with enhanced levels of miR-22 expression in adult cardiomyocytes to identify important pathophysiologic targets of miR-22. Our data shows that forced expression of miR-22 induces a pro-hypertrophic gene expression program, and it elicits contractile dysfunction leading to cardiac dilation and heart failure. Increased expression of miR-22 impairs the Ca(2+) transient, Ca(2+) loading into the sarcoplasmic reticulum plus it interferes with transcription of estrogen related receptor (ERR) and PPAR downstream genes. Mechanistically, miR-22 postranscriptionally inhibits peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1?), PPAR? and sirtuin 1 (SIRT1) expression via a synergistic circuit, which may account for deleterious actions of unchecked miR-22 expression on the heart.

| S-EPMC3785418 | biostudies-literature

Broad-spectrum suppression of bacterial pneumonia by aminoglycoside-propagated Acinetobacter baumannii.

Project description:Antimicrobial resistance is increasing in pathogenic bacteria. Yet, the effect of antibiotic exposure on resistant bacteria has been underexplored and may affect pathogenesis. Here we describe the discovery that propagation of the human pathogen Acinetobacter baumannii in an aminoglycoside antibiotic results in alterations to the bacterium that interact with lung innate immunity resulting in enhanced bacterial clearance. Co-inoculation of mice with A. baumannii grown in the presence and absence of the aminoglycoside, kanamycin, induces enhanced clearance of a non-kanamycin-propagated strain. This finding can be replicated when kanamycin-propagated A. baumannii is killed prior to co-inoculation of mice, indicating the enhanced bacterial clearance results from interactions with innate host defenses in the lung. Infection with kanamycin-propagated A. baumannii alters the kinetics of phagocyte recruitment to the lung and reduces pro- and anti-inflammatory cytokine and chemokine production in the lung and blood. This culminates in reduced histopathologic evidence of lung injury during infection despite enhanced bacterial clearance. Further, the antibacterial response induced by killed aminoglycoside-propagated A. baumannii enhances the clearance of multiple clinically relevant Gram-negative pathogens from the lungs of infected mice. Together, these findings exemplify cooperation between antibiotics and the host immune system that affords protection against multiple antibiotic-resistant bacterial pathogens. Further, these findings highlight the potential for the development of a broad-spectrum therapeutic that exploits a similar mechanism to that described here and acts as an innate immunity modulator.

| S-EPMC7094866 | biostudies-literature

Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential.

Project description:The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent. In this brief review, we summarize the broad antiviral activity of niclosamide and highlight its potential clinical use in the treatment of COVID-19.

| S-EPMC7098069 | biostudies-literature

Xpo7 is a broad-spectrum exportin and a nuclear import receptor.

Project description:Exportins bind cargo molecules in a RanGTP-dependent manner inside nuclei and transport them through nuclear pores to the cytoplasm. CRM1/Xpo1 is the best-characterized exportin because specific inhibitors such as leptomycin B allow straightforward cargo validations in vivo. The analysis of other exportins lagged far behind, foremost because no such inhibitors had been available for them. In this study, we explored the cargo spectrum of exportin 7/Xpo7 in depth and identified not only ∼200 potential export cargoes but also, surprisingly, ∼30 nuclear import substrates. Moreover, we developed anti-Xpo7 nanobodies that acutely block Xpo7 function when transfected into cultured cells. The inhibition is pathway specific, mislocalizes export cargoes of Xpo7 to the nucleus and import substrates to the cytoplasm, and allowed validation of numerous tested cargo candidates. This establishes Xpo7 as a broad-spectrum bidirectional transporter and paves the way for a much deeper analysis of exportin and importin function in the future.

| S-EPMC6028547 | biostudies-literature

CTGF is a therapeutic target for metastatic melanoma.

Project description:Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.

| S-EPMC3965577 | biostudies-literature

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