Delta-Opioid Receptor Activation Promotes Mesenchymal Stem Cell Survival via PKC/STAT3 Signaling Pathway

Higuchi, Sayaka; Masaaki,; Zhu, Ping; Ashraf, Muhammad

doi:10.1253/circj.cj-11-0309

Cited by 21 publications

(8 citation statements)

References 46 publications

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“…In addition, both MSC and osteoblasts expressed PENK processing enzymes PCSK2, CPD, and CPE; however, there were no phenotypic changes in expression of these genes. Gene expression for the dopioid receptor (OPRD) was significantly greater in MSC cultures relative to osteoblasts (p < 0.0146), consistent with previous work 21 (Fig. 1A).…”

Section: Resultssupporting

confidence: 90%

“…Previous studies have not always accounted for the parallel expression of the OGFR with the OPRM, OPRK, OPRD, or precursors to the met5-ligand. [5][6][7][8][9][10][11]21,27 The OPRM and OPRK were not observed in mesenchymal lineage cells whereas the OPRD was expressed in MSC and to a lesser extent in osteoblasts; however, when compared to the OGFR the OPRD was expressed eightfold and 148-fold less, respectively. Opioids bind the OPRD and not the OGFR whereas the met5-ligand will bind both the OPRD and the OGFR.…”

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confidence: 96%

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Antagonism of the Met5‐enkephalin‐opioid growth factor receptor‐signaling axis promotes MSC to differentiate into osteoblasts

Thakur

DeBoyace

Margulies

2015

Journal Orthopaedic Research

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Chronic opioid therapy is associated with bone loss. This led us to hypothesize that the opioid antagonists, that include naloxone, would stimulate bone formation by regulating MSC differentiation. The opioid growth factor receptor (OGFR) is a noncanonical opioid receptor that binds naloxone with high affinity whereas the native opioid growth factor, met5-enkephalin (met5), binds both the OGFR and the canonical delta opioid receptor (OPRD). Naloxone and an shRNA OGFR lentivirus were employed to disrupt the OGFR-signaling axis in cultured MSC. In parallel, naloxone was administered to bone marrow using a mouse unicortical defect model. OPRD, OGFR, and the met5-ligand were highly expressed in MSC and osteoblasts. A pulse-dose of naloxone increased mineral formation in MSC cultures in contrast to MSC treated with continuous naloxone or OGFR deficient MSC. Importantly, SMAD1 and SMAD8/9 expression increased after a pulse dose of naloxone whereas SMAD1, SMAD7, and ID1 were increased in the OGFR deficient MSC. Inhibited OGFR signaling decreased proliferation and increased p21 expression. The addition of naloxone to the unicortical defect resulted in increased bone formation within the defect. Our data suggest that novel mechanism through which signaling through the OGFR regulates osteogenesis via negative regulation of SMAD1 and p21. The opioid growth factor-receptor (OGFR or z-opioid receptor) is a non-canonical, peri-nuclear opioid-receptor that does not share structural homology with the canonical m-, k-, and d-opioid-receptors (OPRM, OPRK, and OPRD, respectively) and binds the native opioid-ligands less efficiently than the canonical opioid receptors.

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Section: Resultssupporting

confidence: 90%

mentioning

confidence: 96%

Antagonism of the Met5‐enkephalin‐opioid growth factor receptor‐signaling axis promotes MSC to differentiate into osteoblasts

Thakur

DeBoyace

Margulies

2015

Journal Orthopaedic Research

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“…One of the potential mechanisms underlying DOR neuroprotection is related to its ability to attenuate ROS oxidative stress and increase antioxidant capacity in the ischaemic brain (Yang et al ., ). As DOR signalling is coupled with PKC (Tang et al ., ; Chao et al ., ; Higuchi et al ., ) and PKC is involved in the function of Nrf2 (Huang et al ., ; Bloom and Jaiswal, ), we hypothesized that DOR could act as an upstream regulator of Nrf2 function and that the DOR‐mediated protection against hypoxic/ischaemic injury was directly related to its interaction with Nrf2.…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism for cytoprotection against hypoxic injury: δ‐opioid receptor‐mediated increase in Nrf2 translocation

Cao

Chao²,

Zhou

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEHypoxia/reoxygenation induces synthesis of reactive oxygen species (ROS) which can attack macromolecules and cause brain injury. The transcription factor, nuclear factor (erythroid-derived 2)-like 2, (Nrf2), ia potent activator of genes with an antioxidant responsive element and Nrf2 can counteract oxidative injury by increasing expression of several antioxidative genes in response to ROS stress. Here, we show that activation of the δ-opioid receptor (DOR) increasedNrf2 protein expression and translocation, thereby leading to cytoprotection. EXPERIMENTAL APPROACHWe used HEK293t cells exposed to 0.5% O2 for 16 h and then reoxygenated for 4 h as a model of hypoxia-reperfusion (H/R) injury. Real time PCR, Western blotting, siRNA and immunohistochemical techniques were used to follow Nrf2 expression and activity. Cell viability and damage (as LDH leakage) were also measured. KEY RESULTSH/R injury triggered Nrf2 translocation into the nucleus and up-regulated expression of several downstream genes, relevant to antioxidation, such as NAD(P)H:quinone oxidoreductase (NQO1). Incubation with the DOR agonist UFP-512 enhanced Nrf2 protein expression and translocation and up-regulated its downstream genes in normoxia and further increased Nrf2 expression and translocation after H/R, protecting the cells against loss of viability and damage. The effect of UFP-512 on Nrf2 nuclear translocation was blocked by the DOR antagonist, naltrindole. Also, DOR-mediated cytoprotection was strongly inhibited after transfection of HEK293t cells with Nrf2 siRNA. CONCLUSIONS AND IMPLICATIONSThe DOR agonist UFP-512 was cytoprotective against H/R injury and this effect was partly dependent on DOR-mediated increase in Nrf2 function. AbbreviationsARE, antioxidant response element; DOR, δ-opioid receptor; GCLC, glutamate-cysteine ligase-catalytic subunit; GCLM, glutamate-cysteine ligase-modifier subunit; H/R, hypoxia-reperfusion; HO-1, haem oxygenase 1; Keap1, Kelch-like ECH associating protein 1; NQO1, NAD(P)H dehydrogenase [quinone] 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; ROS, reactive oxygen species; siRNA, small interfering RNA

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“…This results in differences in the regulation of nociception and emotional responses (50), but also proliferation, differentiation and survival of cells outside the central nervous system (28,51,52).…”

Section: Discussionmentioning

confidence: 99%

Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial-mesenchymal transition

Tripolt

Knab

Neubauer

et al. 2018

Preprint

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The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental facts exist. Expression of δ-opioid receptors (DORs) correlates with poor prognosis for breast cancer (BCa) patients, but mechanism and genetic/pharmacologic proof of key changes in opioid-triggered cancer biology are lacking. We show that oncogenic STAT3 signaling and E-Cadherin downregulation are triggered by opioid-ligated DORs, promoting metastasis. Human and murine transplanted BCa cells (MDA-MB-231, 4T1) displayed enhanced metastasis upon opioid-induced DOR stimulation, and DOR-antagonist blocked metastasis. Opioid-exposed BCa cells showed enhanced migration, STAT3 activation, down-regulation of E-Cadherin and expression of epithelial-mesenchymal transition (EMT) markers. STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced BCa cell metastasis and migration. We conclude that opioids trigger metastasis through oncogenic JAK1/2-STAT3 signaling.

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Delta-Opioid Receptor Activation Promotes Mesenchymal Stem Cell Survival via PKC/STAT3 Signaling Pathway

Cited by 21 publications

References 46 publications

Antagonism of the Met5‐enkephalin‐opioid growth factor receptor‐signaling axis promotes MSC to differentiate into osteoblasts

Antagonism of the Met5‐enkephalin‐opioid growth factor receptor‐signaling axis promotes MSC to differentiate into osteoblasts

A novel mechanism for cytoprotection against hypoxic injury: δ‐opioid receptor‐mediated increase in Nrf2 translocation

Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial-mesenchymal transition

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