Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

Dietrich, Péter; Wormser, Laura; Fritz, Valerie; Seitz, Tatjana; Maria, Monica De; Schambony, Alexandra; Kremer, Andreas E.; Günther, Claudia; Itzel, Timo; Thasler, Wolfgang E.; Teufel, Andreas; Trebicka, Jonel; Hartmann, Arndt; Neurath, Markus F.; Hörsten, Stephan von; Boßerhoff, Anja; Hellerbrand, Claus

doi:10.1172/jci131919

Cited by 31 publications

(40 citation statements)

References 90 publications

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“…Cells were cultured as described [ 32 ]. Primary human hepatocytes (PHH) were isolated and cultured as described [ 51 , 52 ].…”

Section: Methodsmentioning

confidence: 99%

“…For analysis of apoptosis, cells were stained with FITC-conjugated Annexin V and propidium iodide using the Annexin V-FITC Detection Kit (PromoKine, PromoCell GmbH, Heidelberg, Germany) according to the manufacturer’s instructions as described [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial activity of cells was determined using a colorimetric XTT assay (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s protocol, and was described previously [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

“…Cell proliferation was analyzed the using a CyQUANT NF Cell Proliferation Assay Kit (Molecular Probes, Eugene, OR, USA) following the manufacturer’s description as described [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

“…Migratory activity of melanoma cells following treatment with XN for 4 h was quantified using a Boyden chamber assay as described [ 51 ], with DMEM supplemented with 20% FCS attached to the bottom chamber. Further, cell migration was assessed using the Cultrex 96 Well Cell Migration Assay (Trevigen, Gaithersburg, MD, USA) according to the manufacturer’s protocol as described [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

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Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Seitz

Hackl

Freese

et al. 2021

Cancers

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Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju; Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis.

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“…Cells were cultured as described [ 32 ]. Primary human hepatocytes (PHH) were isolated and cultured as described [ 51 , 52 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Cell proliferation was analyzed the using a CyQUANT NF Cell Proliferation Assay Kit (Molecular Probes, Eugene, OR, USA) following the manufacturer’s description as described [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Seitz

Hackl

Freese

et al. 2021

Cancers

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Neuropeptides in Cancer: Friend and Foe?

Berisha

Borniger

2022

Advanced Biology

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highly dynamic network of various cell types (e.g., cancer cells, endothelial cells, immune cells, fibroblasts) that exert differential effects on neuronal activity within the local environment. Thus, complex signaling between cancer and stromal cells in the TME results in altered firing rates of local nerves. Reciprocally, increased neuronal activity and subsequent release of classical neurotransmitters and/or neuropeptides within the TME results in enhanced cancer progression and subsequent metastasis in various preclinical models and clinical studies. [5][6][7][8][9] Nerves interact with multiple stromal cells in the TME where they indirectly promote tumor growth, progression, and subsequent metastasis. [10] Several studies have demonstrated that sympathetic nerve innervation and subsequent release of the neurotransmitter norepinephrine (NE) is increased in breast tumors. [6,8,9] However, recent work has demonstrated that there is an inverse relationship between tumor weight and norepinephrine content (i.e., larger the size of the tumor, the lower the levels of NE), despite increased innervation of sympathetic nerves within the TME. [11] These findings may be attributed to a relatively unexplored phenomenon: neuropeptide release within the TME. Neuropeptides are molecular messengers that regulate a variety of functions in the central and peripheral nervous systems via binding G-protein-coupled receptors (GPCRs) on target cells. One of the many functions of neuropeptides is serving as growth factors for normal cells via the activation of the heterotrimeric G protein Gq and subsequent synthesis of second messengers and engagement of tyrosine phosphorylation cascades. Neuropeptides act as neuromodulators, in that they can alter the response of neurons to neurotransmitters and other circulating signals, such as leptin, ghrelin, glucose, and insulin-all of which are affected during cancer progression. [12][13][14][15][16][17] For example, both neuropeptide Y (NPY) and hypocretin/orexin neurons appear to mediate some of the orexigenic effects of centrally administered ghrelin as administration of NPY receptor antagonists attenuated ghrelininduced feeding. Similarly, ghrelin-induced feeding was suppressed in orexin knockout mice, indicating that ghrelin may stimulate feeding through both the orexin and NPY systems. [18] However, neuropeptide signaling is exploited within cancer cells and many studies demonstrate the contribution of neuropeptides in tumor cell proliferation and migration, [19] with many major neuropeptides also potentially contributing to cancer processes (see Table 1). Additionally, neuropeptides exert direct Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptid...

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Binding of Natural Peptide Ligands to the Neuropeptide Y₅ Receptor

Rudolf

Kaempf

et al. 2021

Angewandte Chemie

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The binding mode of natural peptide ligands to the Y 5 Gprotein-coupled receptor (Y 5 R), an attractive therapeutic target for the treatment of obesity,islargely unknown. Here,we apply complementary biochemical and computational approaches,i ncluding scanning of the receptor surface with ag enetically encoded crosslinker,A la-scanning of the ligand and double-cycle mutagenesis,t om ap interactions in the ligand-receptor interface and build as tructural model of the NPY-Y 5 Rc omplex guided by the experimental data. In the model, the carboxyl (C)-terminus of bound NPY is placed close to the extracellular loop (ECL) 3, whereas the characteristic a-helical segment of the ligand drapes over ECL1 and is tethered towards ECL2 by ah ydrophobic cluster.W ef urther show that the other two natural ligands of Y 5 R, peptide YY (PYY) and pancreatic polypeptide (PP) dock to the receptor in asimilar pose.

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Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

Cited by 31 publications

References 90 publications

Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Neuropeptides in Cancer: Friend and Foe?

Binding of Natural Peptide Ligands to the Neuropeptide Y₅ Receptor

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Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

Cited by 31 publications

References 90 publications

Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Neuropeptides in Cancer: Friend and Foe?

Binding of Natural Peptide Ligands to the Neuropeptide Y5 Receptor

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Product

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About

Binding of Natural Peptide Ligands to the Neuropeptide Y₅ Receptor