scholarly journals Ion Channels in The Pathogenesis of Endometriosis: A Cutting-Edge Point of View

2020 ◽  
Vol 21 (3) ◽  
pp. 1114 ◽  
Author(s):  
Gaetano Riemma ◽  
Antonio Simone Laganà ◽  
Antonio Schiattarella ◽  
Simone Garzon ◽  
Luigi Cobellis ◽  
...  
Keyword(s):  
Ion Channels ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Urokinase Plasminogen Activator Receptor ◽  
Direct Role ◽  
Ectopic Endometrium

Background: Ion channels play a crucial role in many physiological processes. Several subtypes are expressed in the endometrium. Endometriosis is strictly correlated to estrogens and it is evident that expression and functionality of different ion channels are estrogen-dependent, fluctuating between the menstrual phases. However, their relationship with endometriosis is still unclear. Objective: To summarize the available literature data about the role of ion channels in the etiopathogenesis of endometriosis. Methods: A search on PubMed and Medline databases was performed from inception to November 2019. Results: Cystic fibrosis transmembrane conductance regulator (CFTR), transient receptor potentials (TRPs), aquaporins (AQPs), and chloride channel (ClC)-3 expression and activity were analyzed. CFTR expression changed during the menstrual phases and was enhanced in endometriosis samples; its overexpression promoted endometrial cell proliferation, migration, and invasion throughout nuclear factor kappa-light-chain-enhancer of activated B cells-urokinase plasminogen activator receptor (NFκB-uPAR) signaling pathway. No connection between TRPs and the pathogenesis of endometriosis was found. AQP5 activity was estrogen-increased and, through phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT), helped in vivo implantation of ectopic endometrium. In vitro, AQP9 participated in extracellular signal-regulated kinases/p38 mitogen-activated protein kinase (ERK/p38 MAPK) pathway and helped migration and invasion stimulating matrix metalloproteinase (MMP)2 and MMP9. ClC-3 was also overexpressed in ectopic endometrium and upregulated MMP9. Conclusion: Available evidence suggests a pivotal role of CFTR, AQPs, and ClC-3 in endometriosis etiopathogenesis. However, data obtained are not sufficient to establish a direct role of ion channels in the etiology of the disease. Further studies are needed to clarify this relationship.

scholarly journals Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Shan Lei ◽  
Zhiwei He ◽  
Tengxiang Chen ◽  
Xingjun Guo ◽  
Zhirui Zeng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Migration And Invasion ◽  
Potential Biomarker

Abstract Background Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies

2008 ◽  
Vol 413 (3) ◽  
pp. 429-436 ◽  
Author(s):  
Yan Zeng ◽  
Heidi Sankala ◽  
Xiaoxiao Zhang ◽  
Paul R. Graves
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Processing Bodies ◽  
Mitogen Activated Protein

Ago (Argonaute) proteins are essential effectors of RNA-mediated gene silencing. To explore potential regulatory mechanisms for Ago proteins, we examined the phosphorylation of human Ago2. We identified serine-387 as the major Ago2 phosphorylation site in vivo. Phosphorylation of Ago2 at serine-387 was significantly induced by treatment with sodium arsenite or anisomycin, and arsenite-induced phosphorylation was inhibited by a p38 MAPK (mitogen-activated protein kinase) inhibitor, but not by inhibitors of JNK (c-Jun N-terminal kinase) or MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]. MAPKAPK2 (MAPK-activated protein kinase-2) phosphorylated bacterially expressed full-length human Ago2 at serine-387 in vitro, but not the S387A mutant. Finally, mutation of serine-387 to an alanine residue or treatment of cells with a p38 MAPK inhibitor reduced the localization of Ago2 to processing bodies. These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway.

scholarly journals Methionine Sulfoxide Reductase B1 Regulates Hepatocellular Carcinoma Cell Proliferation and Invasion via the Mitogen-Activated Protein Kinase Pathway and Epithelial-Mesenchymal Transition

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Qiang He ◽  
Hui Li ◽  
Fanzhi Meng ◽  
Xiangjun Sun ◽  
Xu Feng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Methionine sulfoxide reductase B1 (MsrB1) is a member of the selenoprotein family, which contributes to the reduction of methionine sulfoxides produced from reactive oxygen species (ROS) by redox processes in energy pathways. However, few studies have examined the role of MsrB1 in human hepatocellular carcinoma (HCC). We observed that MsrB1 is highly expressed in HCC tissues and that its expression correlated with the prognoses of patients with HCC after hepatectomy. In vitro, knockdown of MsrB1 inhibits HCC cell growth by MTT and EdU proliferation assay, and MsrB1 interference enhances H2O2/trx-induced apoptosis. We observed that phosphorylation of the key proteins of the MAPK pathway, namely, ERK, MEK, and p53, was inhibited, but PARP and caspase 3 were increased, thus infecting mitochondrial integrity. In vivo, MsrB1 knockdown effectively inhibited tumor growth. Furthermore, MsrB1 knockdown reduced HCC cell migration and invasion in a transwell assay through inhibition of cytoskeletal rearrangement and spread. This change was linked to epithelial-mesenchymal transition (EMT) inhibition resulting from increases in E-cadherin expression and decreases in expression in TGF-β1, Slug, MMP-2/9, and so on. MsrB1 regulates HCC cell proliferation and migration by modulating the MAPK pathway and EMT. Thus, MsrB1 may be a novel therapeutic target with respect to the treatment of HCC.

scholarly journals Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

2006 ◽  
Vol 11 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Charlotta Grånäs ◽  
Betina Kerstin Lundholt ◽  
Frosty Loechel ◽  
Hans-Christian Pedersen ◽  
Sara Petersen Bjørn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

Role of mitogen-activated protein kinase pathway in acetylcholine-mediated in vitro relaxation of rat pulmonary artery

2002 ◽  
Vol 434 (1-2) ◽  
pp. 55-64 ◽  
Author(s):  
Wai Yee Choy ◽  
Yung Fat Wong ◽  
Yiu Wa Kwan ◽  
Alice Lai Shan Au ◽  
Wing Hung Lau ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pulmonary Artery ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

scholarly journals Celecoxib as a Valuable Adjuvant in Cutaneous Melanoma Treated with Trametinib

2021 ◽  
Vol 22 (9) ◽  
pp. 4387
Author(s):  
Diana Valentina Tudor ◽  
Ioana Bâldea ◽  
Diana Elena Olteanu ◽  
Eva Fischer-Fodor ◽  
Virag Piroska ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Human Fibroblasts ◽  
In Vitro Study ◽  
Melanoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Culture Cells ◽  
Nm Range

Background: Melanoma patients stop responding to targeted therapies mainly due to mitogen activated protein kinase (MAPK) pathway re-activation, phosphoinositide 3 kinase/the mechanistic target of rapamycin (PI3K/mTOR) pathway activation or stromal cell influence. The future of melanoma treatment lies in combinational approaches. To address this, our in vitro study evaluated if lower concentrations of Celecoxib (IC50 in nM range) could still preserve the chemopreventive effect on melanoma cells treated with trametinib. Materials and Methods: All experiments were conducted on SK-MEL-28 human melanoma cells and BJ human fibroblasts, used as co-culture. Co-culture cells were subjected to a celecoxib and trametinib drug combination for 72 h. We focused on the evaluation of cell death mechanisms, melanogenesis, angiogenesis, inflammation and resistance pathways. Results: Low-dose celecoxib significantly enhanced the melanoma response to trametinib. The therapeutic combination reduced nuclear transcription factor (NF)–kB (p < 0.0001) and caspase-8/caspase-3 activation (p < 0.0001), inhibited microphthalmia transcription factor (MITF) and tyrosinase (p < 0.05) expression and strongly down-regulated the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway more significantly than the control or trametinib group (p < 0.0001). Conclusion: Low concentrations of celecoxib (IC50 in nM range) sufficed to exert antineoplastic capabilities and enhanced the therapeutic response of metastatic melanoma treated with trametinib.

scholarly journals Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells

2010 ◽  
Vol 429 (3) ◽  
pp. 565-572 ◽  
Author(s):  
Ian M. Evans ◽  
Azadeh Bagherzadeh ◽  
Mark Charles ◽  
Tony Raynham ◽  
Chris Ireson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase ◽  
Umbilical Vein ◽  
Biological Effects ◽  
Camp Response Element Binding ◽  
Mitogen Activated Protein Kinase ◽  
Protein Kinase D ◽  
Vegf Receptor

VEGF (vascular endothelial growth factor) plays an essential role in angiogenesis during development and in disease largely mediated by signalling events initiated by binding of VEGF to its receptor, VEGFR2 (VEGF receptor 2)/KDR (kinase insert domain receptor). Recent studies indicate that VEGF activates PKD (protein kinase D) in endothelial cells to regulate a variety of cellular functions, including signalling events, proliferation, migration and angiogenesis. To better understand the role of PKD in VEGF-mediated endothelial function, we characterized the effects of a novel pyrazine benzamide PKD inhibitor CRT5 in HUVECs (human umbilical vein endothelial cells). The activity of the isoforms PKD1 and PKD2 were blocked by this inhibitor as indicated by reduced phosphorylation, at Ser916 and Ser876 respectively, after VEGF stimulation. The VEGF-induced phosphorylation of three PKD substrates, histone deacetylase 5, CREB (cAMP-response-element-binding protein) and HSP27 (heat-shock protein 27) at Ser82, was also inhibited by CRT5. In contrast, CRT6, an inactive analogue of CRT5, had no effect on PKD or HSP27 Ser82 phosphorylation. Furthermore, phosphorylation of HSP27 at Ser78, which occurs solely via the p38 MAPK (mitogen-activated protein kinase) pathway, was also unaffected by CRT5. In vitro kinase assays show that CRT5 did not significantly inhibit several PKC isoforms expressed in endothelial cells. CRT5 also decreased VEGF-induced endothelial migration, proliferation and tubulogenesis, similar to effects seen when the cells were transfected with PKD siRNA (small interfering RNA). CRT5, a novel specific PKD inhibitor, will greatly facilitate the study of the role of PKD signalling mechanisms in angiogenesis.

scholarly journals Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro

1998 ◽  
Vol 95 (13) ◽  
pp. 7422-7426 ◽  
Author(s):  
L. Shapiro ◽  
K. A. Heidenreich ◽  
M. K. Meintzer ◽  
C. A. Dinarello
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Hiv Type 1

Mitogen-activated Protein Kinase 7 Promotes Cell Proliferation, Migration and Invasion in SOSP-M Human Osteosarcoma Cell Line

2015 ◽  
Vol 103 (5) ◽  
pp. 483-488 ◽  
Author(s):  
Yan Huang ◽  
Jianhua Yao ◽  
Bing Zhu ◽  
Jianzheng Zhang ◽  
Tiansheng Sun
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Expression Level ◽  
Migration And Invasion ◽  
M Cells ◽  
Rt Pcr ◽  
Blank Group ◽  
Mitogen Activated Protein

Purpose Osteosarcoma (OS) is the most common primary bone tumor and has low cure rates. Our study aimed to evaluate the roles of mitogen-activated protein kinase 7 (MAPK7) in cell proliferation, migration and invasion using the SOSP-M human OS cell line as an in vitro model. Methods SOSP-M cells were transfected with PCDNA3.1-MAPK7 and siRNA-MAPK7 plasmids using Lipofectamine 2000. Quantitative real-time polymerase chain reaction (RT-PCR) was performed to determine the relative expression level of MAPK7 and Western blot analysis was carried out to determine the expression level of ERK5 protein. Then MTT, scratch wound healing and Matrigel transwell assays were used to investigate the roles of MAPK7 expression in the proliferation, migration and invasion, respectively, of SOSP-M cells in vitro. Results RT-PCR analysis showed that the expression level of MAPK7 increased significantly after transfection with PCDNA3.1-MAPK7 plasmid compared with the blank group, while it decreased significantly after transfection with siRNA-MAPK7 plasmid. Similar results for ERK5 expression were obtained by Western blot analysis. In addition, the cell proliferation rate, cell migration rate and invasive cell number in the PCDNA3.1-MAPK7 transfection group increased significantly compared with the blank group, while they decreased significantly in the siRNA-MAPK7 transfection group. Conclusions Our results indicate that overexpression of MAPK7 in human OS cells could promote cell proliferation, migration and invasion, whereas knockdown of MAPK7 expression had the opposite effect. All the results suggest that MAPK7 may serve as a potent target for drug development.

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