Upregulation of the δ opioid receptor in liver cancer promotes liver cancer progression both in vitro and in vivo

The δ-opioid receptor (δOR) holds great potential as a therapeutic target. Yet, clinical drug development, which has focused on δOR agonists that mimic the potent and selective tool compound SNC80 have largely failed. It has increasingly become apparent that the SNC80 scaffold carries with it potent and efficacious β-arrestin recruitment. Here, we screened a relatively small (5120 molecules) physical drug library to identify δOR agonists that underrecruit β-arrestin, as it has been suggested that compounds that efficaciously recruit β-arrestin are proconvulsant. The screen identified a hit compound and further characterization using cellular binding and signaling assays revealed that this molecule (R995045, compound 1) exhibited ten-fold selectivity over µ- and κ-opioid receptors. Compound 1 represents a novel chemotype at the δOR. A subsequent characterization of fourteen analogs of compound 1, however did not identify a more potent δOR agonist. Computational modeling and in vitro characterization of compound 1 in the presence of the endogenous agonist leu-enkephalin suggest compound 1 may also bind allosterically and negatively modulate the potency of Leu-enkephalin to inhibit cAMP, acting as a ‘NAM-agonist’ in this assay. The potential physiological utility of such a class of compounds will need to be assessed in future in vivo assays.

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Asymmetric Synthesis and in Vitro and in Vivo Activity of Tetrahydroquinolines Featuring a Diverse Set of Polar Substitutions at the 6 Position as Mixed-Efficacy μ Opioid Receptor/δ Opioid Receptor Ligands

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.5b00100 ◽

2015 ◽

Vol 6 (8) ◽

pp. 1428-1435 ◽

Cited By ~ 22

Author(s):

Aaron M. Bender ◽

Nicholas W. Griggs ◽

Jessica P. Anand ◽

John R. Traynor ◽

Emily M. Jutkiewicz ◽

...

Keyword(s):

Asymmetric Synthesis ◽

Opioid Receptor ◽

Receptor Ligands ◽

Opioid Receptor Ligands ◽

Μ Opioid Receptor ◽

Mixed Efficacy ◽

Δ Opioid Receptor

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Analogues of cholecystokinin 26–33 selective for B-type CCK receptors possess δ opioid receptor agonist activity in vitro and in vivo: Evidence for similarities in CCK-B and δ opioid receptor requirements

Peptides ◽

10.1007/978-94-011-0683-2_221 ◽

1994 ◽

pp. 669-671 ◽

Cited By ~ 3

Author(s):

V. J. Hruby ◽

S. N. Fang ◽

T. H. Kramer ◽

P. Davis ◽

D. Parkhurst ◽

...

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Agonist Activity ◽

Cck Receptors ◽

Opioid Receptor Agonist ◽

Δ Opioid Receptor

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Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015335 ◽

2020 ◽

pp. jbc.RA120.015335

Author(s):

Yuan Deng ◽

Ming Li ◽

Minghui Zhuo ◽

Peng Guo ◽

Qiang Chen ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Progression ◽

Liver Tumors ◽

The Self ◽

High Rate ◽

Sox9 Expression ◽

Self Renewal ◽

Lysine Demethylase

Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Mechanistically, JMJD2D promoted LCSC self-renewal by enhancing the expression of CSC markers EpCAM and Sox9; JMJD2D reduced H3K9me3 levels on the promoters of EpCAM and Sox9 to enhance their transcription via interaction with β-catenin/TCF4 and Notch1 intracellular domain, respectively. Restoration of EpCAM and Sox9 expression in JMJD2D-knockdown liver cancer cells rescued the self-renewal of LCSCs. Pharmacological inhibition of JMJD2D using 5-c-8HQ reduced the self-renewal of LCSCs and liver cancer progression. Collectively, our findings suggest that JMJD2D promotes LCSC self-renewal by enhancing EpCAM and Sox9 expression via Wnt/β-catenin and Notch signaling pathways and is a potential therapeutic target for liver cancer.

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Immunofluorescence analysis of antisense oligodeoxynucleotide-mediated ‘knock-down’ of the mouse δ opioid receptor in vitro and in vivo

Neuroscience Letters ◽

10.1016/0304-3940(96)12883-4 ◽

1996 ◽

Vol 213 (3) ◽

pp. 205-208

Author(s):

Josephine Lai ◽

Maureen Riedl ◽

Laura S. Stone ◽

Ulf Arvidsson ◽

Edward J. Bilsky ◽

...

Keyword(s):

Opioid Receptor ◽

Antisense Oligodeoxynucleotide ◽

Immunofluorescence Analysis ◽

Knock Down ◽

Δ Opioid Receptor

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In vitro and in vivo pharmacological profile of UFP-512, a novel selective δ-opioid receptor agonist; correlations between desensitization and tolerance

British Journal of Pharmacology ◽

10.1038/sj.bjp.0707613 ◽

2007 ◽

Vol 152 (8) ◽

pp. 1325-1325 ◽

Cited By ~ 2

Author(s):

B Aguila ◽

L Coulbault ◽

M Boulouard ◽

F Léveillé ◽

A Davis ◽

...

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Pharmacological Profile ◽

Opioid Receptor Agonist ◽

Δ Opioid Receptor

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In vivo and in vitro inhibition of human liver cancer progress by downregulation of the μ-opioid receptor and relevant mechanisms

Oncology Reports ◽

10.3892/or.2013.2640 ◽

2013 ◽

Vol 30 (4) ◽

pp. 1731-1738 ◽

Cited By ~ 11

Author(s):

JIN LU ◽

ZEFENG LIU ◽

LINGLING ZHAO ◽

HUIMIN TIAN ◽

XIUHUA LIU ◽

...

Keyword(s):

Liver Cancer ◽

Opioid Receptor ◽

Human Liver ◽

Human Liver Cancer ◽

Μ Opioid Receptor ◽

In Vitro Inhibition

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Recreating Tumour Complexity in a Dish: Organoid Models to Study Liver Cancer Cells and their Extracellular Environment

Cancers ◽

10.3390/cancers11111706 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1706 ◽

Cited By ~ 7

Author(s):

van Tienderen ◽

Groot Koerkamp ◽

IJzermans ◽

van der Laan ◽

Verstegen

Keyword(s):

Liver Cancer ◽

Cancer Progression ◽

Primary Liver Cancer ◽

Tumour Microenvironment ◽

In Vitro Models ◽

Experimental Models ◽

Liver Tumours ◽

Extracellular Environment

Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro models that can recapitulate the tumour are essential in increasing our understanding of liver cancer. Herein, primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumour properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumour microenvironment. However, the extracellular component also plays a vital role in cancer progression and representation is lacking within current in vitro models. In this review, organoid technology is discussed in the context of liver cancer models through comparisons to other cell culture systems. In addition, the role of the tumour extracellular environment in primary liver cancer will be highlighted with an emphasis on its importance in in vitro modelling. Converging novel organoid-based models with models incorporating the native tumour microenvironment could lead to experimental models that can better recapitulate liver tumours in vivo.

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