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Yutong Zhao - One of the best experts on this subject based on the ideXlab platform.
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A blocking peptide stabilizes Lysophosphatidic Acid Receptor 1 and promotes Lysophosphatidic Acid-induced cellular responses.
Journal of cellular biochemistry, 2021Co-Authors: Sarah J Taleb, Su Dong, Jing Zhao, Jianxin Wei, Rachel K Mialki, Yutong ZhaoAbstract:G protein-coupled Receptors regulate a variety of cellular responses and have been considered as therapeutic targets for human diseases. Lysophosphatidic Acid Receptor 1 (LPA1) is a Receptor for bioactive lysophospholipid, LPA. LPA/LPA1-mediated signaling contributes to inflammatory and fibrotic responses in lung diseases; thus understanding regulation of LPA1 stability is important for modulating LPA/LPA1 signaling. Our previous study has shown that LPA1 is degraded in the Nedd4 like (Nedd4L) E3 ubiquitin ligase-mediated ubiquitin-proteasome system. In the current study, we attempt to identify a peptide that stabilizes LPA1 through disrupting LPA1 association with Nedd4L. LPA treatment induces both endogenous and overexpressed LPA1 degradation, which is attenuated by a proteasome inhibitor, suggesting that LPA1 is degraded in the proteasome. LPA increases phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and I-κB kinase in lung epithelial cells, and this effect is promoted by overexpression of a peptide (P1) that mimics C-terminal of LPA1. P1, not a control peptide, attenuates LPA-induced LPA1 ubiquitination and degradation, suggesting that P1 stabilizes LPA1. Further, P1 diminishes Nedd4L-mediated degradation of LPA1 and Nedd4L/LPA1 association. In addition to increasing LPA1 signaling, P1 enhances LPA-induced cell migration and gene expression of Elafin, matrix metallopeptidase 1, and serpin family B member 2 in lung epithelial cells. These data suggest that disruption of LPA1 interaction with Nedd4L by P1 increases LPA1 stability and LPA/LPA1 signaling.
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Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.
EBioMedicine, 2016Co-Authors: Jing Zhao, Su Dong, Rachel K. Bowser, Anastasia M. Jacko, Lina Zhang, Yutong ZhaoAbstract:Lysophosphatidic Acid Receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury.
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Molecular regulation of G-protein-coupled Receptor, Lysophosphatidic Acid Receptor 1, trafficking to the cell surface.
The FASEB Journal, 2015Co-Authors: Jing Zhao, Rachel K. Bowser, Jianxin Wei, Yutong ZhaoAbstract:Background: The expression levels of G-protein-coupled Receptors (GPCRs) on the cell surface determine the effects of ligand-induced cellular responses. The Lysophosphatidic Acid Receptor 1 (LPA1),...
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MOLECULAR REGULATION OF Lysophosphatidic Acid Receptor 1 TRAFFICKING TO THE CELL SURFACE
Cellular signalling, 2014Co-Authors: Jing Zhao, Su Dong, Rachel K. Bowser, Jianxin Wei, Shuqi Xiao, Yutong ZhaoAbstract:The Lysophosphatidic Acid Receptor 1 (LPA1), a G-protein coupled Receptor, regulates cell proliferation, migration, and cytokine release. Here, we investigate the molecular signature of LPA1 trafficking to the cell surface. The overexpressed LPA1 with a C-terminal V5 tag (LPA1-V5) is majorly expressed on the cell surface, while two deletion mutants (C320 and ∆84-87) failed to be trafficked to the cell surface. Further, site-directed mutagenesis analysis of the LPA1 revealed that Ile325, Tyr85, and Leu87 within these two fragments regulate LPA1 maturation and trafficking to the cell surface. Over-expression of Sar1, a component of coat protein complex II (COPII), enhances glycosylation of LPA1 wild type, but not these mutants. The mutants of LPA1 are majorly localized in the endoplasmic reticulum (ER) and exhibit a higher binding affinity to heat shock protein 70 (Hsp70), when compared to the LPA1 wild type. Further, we found that all these mutants failed to increase phosphorylation of Erk, and the cytokine release in response to LPA treatment. These results suggest that Ile325, Tyr85, and Leu87 within LPA1 are essential for LPA1 protein properly folding in the ER.
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Integrin signalling regulates the nuclear localization and function of the Lysophosphatidic Acid Receptor-1 (LPA1) in mammalian cells
The Biochemical journal, 2006Co-Authors: Catherine M. Waters, Yutong Zhao, Bahman Saatian, Noreen A. Moughal, Gabor Tigyi, Viswanathan Natarajan, Susan Pyne, Nigel J. PyneAbstract:We show that LPA1 (Lysophosphatidic Acid Receptor-1) is constitutively localized in the nucleus of mammalian cells. LPA1 also traffics from cell membranes to the nucleus in response to LPA (Lysophosphatidic Acid). Several lines of evidence suggest an important role for cell-matrix interaction in regulating the constitutive nuclear localization of LPA1. First, the RGDS peptide, which blocks cell matrix-induced integrin clustering and cytoskeletal rearrangement, reduced the number of cells containing LPA1 in the nucleus. Secondly, a higher proportion of cells contained nuclear LPA1 when adhesion on fibronectin-coated glass was compared with adherence to polylysine-coated glass. Thirdly, pre-treatment of cells with the Rho kinase inhibitor (Y27632) or the myosin light chain kinase inhibitor (ML9) reduced the number of cells containing nuclear LPA1. The addition of LPA and/or Ki16425 (which binds to LPA1) to isolated nuclei containing LPA1 induced the phosphorylation of several proteins with molecular masses of 34, 32, 14 and 11 kDa. These findings demonstrate that trafficking of LPA1 to the nucleus is influenced by cell-matrix interactions and that nuclear LPA1 may be involved in regulating intranuclear protein phosphorylation and signalling.
Hiroshi Ueda - One of the best experts on this subject based on the ideXlab platform.
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abrogation of Lysophosphatidic Acid Receptor 1 ameliorates murine vasculitis
Arthritis Research & Therapy, 2019Co-Authors: Hiroshi Ueda, Jun Nagai, Jerold Chun, Chie Miyabe, Yoshishige Miyabe, Noriko N Miura, Naohito Ohno, Ryoji Tsuboi, Masayuki MiyasakaAbstract:Lysophosphatidic Acid (LPA), generated by autotaxin (ATX), is a bioactive lipid mediator that binds to the Receptors (LPA1–6), and serves as an important mediator in inflammation. Previous studies have demonstrated that LPA-LPA1 cascade contributes to arthritis and skin sclerosis. In this study, we examined the role of LPA signals in murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis. ATX and LPA Receptor expressions were analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Effects of LPA1 inhibition on CAWS-induced vasculitis were evaluated in LPA1-deficient mice or using an LPA1 antagonist, LA-01. Migration activity was assessed using a chemotaxis chamber. The number of migrated fluorescently labeled neutrophils, which were transferred into the vasculitis mice, was counted in the aortic wall. CXCL1 and IL-8 concentrations were determined by enzyme-linked immunosorbent assay. ATX and LPA1 were highly expressed in the inflamed region of CAWS-induced vasculitis. Severity of the vasculitis in LPA1-deficient mice was suppressed. The LPA1 antagonist, LA-01, also ameliorated the CAWS-induced vasculitis. LPA induced neutrophil migration, which was inhibited by LA-01 in vitro. Infiltration of transferred neutrophils from LPA1-deficient mice into the coronary arteries was suppressed. LA-01 also inhibited the infiltration of wild-type neutrophils. Expression of CXCL1 and IL-8 in human endothelial cells was enhanced by LPA, but was inhibited by LA-01. ATX and LPA1 expression levels were higher in the affected skin region of vasculitis patients than in healthy controls. These results suggest that LPA-LPA1 signaling contributes to the development of vasculitis via chemoattractant production from endothelial cells followed by neutrophil recruitment. Thus, LPA1 has potential as a novel target for vasculitis therapies.
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Lysophosphatidic Acid LPA1 and LPA3 Receptors play roles in the maintenance of late tissue plasminogen activator-induced central poststroke pain in mice
Elsevier, 2019Co-Authors: Hiroshi Ueda, Hiroyuki Neyama, Keita Sasaki, Chiho Miyama, Ryusei IwamotoAbstract:We developed a mouse model for central post-stroke pain (CPSP), a centrally-originated neuropathic pain (NeuP). In this mode, mice were first injected with Rose Bengal, followed by photo-irradiation of left middle cerebral artery (MCA) to generate thrombosis. Although the MCA thrombosis was soon dissolved, the reduced blood flow remained for more than 24 h due to subsequent occlusion of microvessels. This photochemically induced thrombosis (PIT) model showed a hypersensitivity to the electrical stimulation of both sides of paw, but did not show any abnormal pain in popular thermal or mechanical nociception tests. When tissue-type plasminogen activator (tPA) was injected 6 h after the PIT stress, tPA-dependent hypersensitivity to the electrical paw stimulation and stable thermal and mechanical hyperalgesia on both sides for more than 17 or 18 days after the PIT treatment. These hyperalgesic effects were abolished in Lysophosphatidic Acid Receptor 1 (LPA1)- and Lysophosphatidic Acid Receptor 3 (LPA3)-deficient mice. When Ki-16425, an LPA1 and LPA3 antagonist was treated twice daily for 6 days consecutively, the thermal and mechanical hyperalgesia at day 17 and 18 were significantly reversed. The liquid chromatography–mass spectrometry (LC–MS/MS) analysis revealed that there is a significant increase in several species of LPA molecules in somatosensory S-I and medial dorsal thalamus (MD), but not in striatum or ventroposterior thalamus. All these results suggest that LPA1 and LPA3 signaling play key roles in the development and maintenance of CPSP. Keywords: Central poststroke pain, Lysophosphatidic Acid, LC–MS/MS, Photochemically induced thrombosis, tP
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Descriptor-based Fitting of Lysophosphatidic Acid Receptor 3 Antagonists into a Single Predictive Mathematical Model
2014Co-Authors: Olaposi I. Omotuyi, Hiroshi UedaAbstract:Abstract—Sixty six diverse compounds previously reported as Lysophosphatidic Acid Receptor (LPA3) inhibitors have been used to derive a mathematical model based on partial least square (PLS) clustering of 41 molecular descriptors and pIC50 values. The preand postcross-validated correlation coefficient (R) is 0.94462 (RMSE=0.21390) and 0.74745 (RMSE=0.49055) respectively. Bivariate contingency analysis tools implemented in MOE was used to prune the descriptors and refit the equations at a descriptor-pIC50 correlation coefficient of 0.8 cutoff. A new equation was derived with R and RMSE values estimated at 0.88074 and 0.31388 respectively. Both equations correctly predicted the 95% of the pIC50 values of the test dataset. Principal component analysis (PCA) was also used to reduce the dimension and linearly transform the raw data; 8 principal components sufficiently account for more than 98% of the variance of the dataset. The numerical model derived here may be adapted for screening chemical database for LPA3 antagonism.
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autotaxin and Lysophosphatidic Acid1 Receptor mediated demyelination of dorsal root fibers by sciatic nerve injury and intrathecal lysophosphatidylcholine
Molecular Pain, 2010Co-Authors: Jun Nagai, Hitoshi Uchida, Yosuke Matsushita, Ryo Yano, Mutsumi Ueda, Masami Niwa, Junken Aoki, Jerold Chun, Hiroshi UedaAbstract:Background Although neuropathic pain is frequently observed in demyelinating diseases such as Guillain-Barre syndrome and multiple sclerosis, the molecular basis for the relationship between demyelination and neuropathic pain behaviors is poorly understood. Previously, we found that Lysophosphatidic Acid Receptor (LPA1) signaling initiates sciatic nerve injury-induced neuropathic pain and demyelination.
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Peripheral mechanisms of neuropathic pain – involvement of Lysophosphatidic Acid Receptor-mediated demyelination
Molecular pain, 2008Co-Authors: Hiroshi UedaAbstract:Recent advances in pain research provide a clear picture for the molecular mechanisms of acute pain; substantial information concerning plasticity that occurs during neuropathic pain has also become available. The peripheral mechanisms responsible for neuropathic pain are found in the altered gene/protein expression of primary sensory neurons. With damage to peripheral sensory fibers, a variety of changes in pain-related gene expression take place in dorsal root ganglion neurons. These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications – decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions. Another characteristic change is observed in allodynia, the functional change of tactile to nociceptive perception. Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms. Because neuropathic pain in peripheral and central demyelinating diseases develops as a result of aberrant myelination in experimental animals, demyelination seems to be a key mechanism of plasticity in neuropathic pain. More recently, we discovered that Lysophosphatidic Acid Receptor activation initiates neuropathic pain, as well as possible peripheral mechanims of demyelination after nerve injury. These results lead to further hypotheses of physical communication between innocuous Aβ- and noxious C- or Aδ-fibers to influence the molecular mechanisms of allodynia.
Jing Zhao - One of the best experts on this subject based on the ideXlab platform.
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A blocking peptide stabilizes Lysophosphatidic Acid Receptor 1 and promotes Lysophosphatidic Acid-induced cellular responses.
Journal of cellular biochemistry, 2021Co-Authors: Sarah J Taleb, Su Dong, Jing Zhao, Jianxin Wei, Rachel K Mialki, Yutong ZhaoAbstract:G protein-coupled Receptors regulate a variety of cellular responses and have been considered as therapeutic targets for human diseases. Lysophosphatidic Acid Receptor 1 (LPA1) is a Receptor for bioactive lysophospholipid, LPA. LPA/LPA1-mediated signaling contributes to inflammatory and fibrotic responses in lung diseases; thus understanding regulation of LPA1 stability is important for modulating LPA/LPA1 signaling. Our previous study has shown that LPA1 is degraded in the Nedd4 like (Nedd4L) E3 ubiquitin ligase-mediated ubiquitin-proteasome system. In the current study, we attempt to identify a peptide that stabilizes LPA1 through disrupting LPA1 association with Nedd4L. LPA treatment induces both endogenous and overexpressed LPA1 degradation, which is attenuated by a proteasome inhibitor, suggesting that LPA1 is degraded in the proteasome. LPA increases phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and I-κB kinase in lung epithelial cells, and this effect is promoted by overexpression of a peptide (P1) that mimics C-terminal of LPA1. P1, not a control peptide, attenuates LPA-induced LPA1 ubiquitination and degradation, suggesting that P1 stabilizes LPA1. Further, P1 diminishes Nedd4L-mediated degradation of LPA1 and Nedd4L/LPA1 association. In addition to increasing LPA1 signaling, P1 enhances LPA-induced cell migration and gene expression of Elafin, matrix metallopeptidase 1, and serpin family B member 2 in lung epithelial cells. These data suggest that disruption of LPA1 interaction with Nedd4L by P1 increases LPA1 stability and LPA/LPA1 signaling.
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Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.
EBioMedicine, 2016Co-Authors: Jing Zhao, Su Dong, Rachel K. Bowser, Anastasia M. Jacko, Lina Zhang, Yutong ZhaoAbstract:Lysophosphatidic Acid Receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury.
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Molecular regulation of G-protein-coupled Receptor, Lysophosphatidic Acid Receptor 1, trafficking to the cell surface.
The FASEB Journal, 2015Co-Authors: Jing Zhao, Rachel K. Bowser, Jianxin Wei, Yutong ZhaoAbstract:Background: The expression levels of G-protein-coupled Receptors (GPCRs) on the cell surface determine the effects of ligand-induced cellular responses. The Lysophosphatidic Acid Receptor 1 (LPA1),...
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MOLECULAR REGULATION OF Lysophosphatidic Acid Receptor 1 TRAFFICKING TO THE CELL SURFACE
Cellular signalling, 2014Co-Authors: Jing Zhao, Su Dong, Rachel K. Bowser, Jianxin Wei, Shuqi Xiao, Yutong ZhaoAbstract:The Lysophosphatidic Acid Receptor 1 (LPA1), a G-protein coupled Receptor, regulates cell proliferation, migration, and cytokine release. Here, we investigate the molecular signature of LPA1 trafficking to the cell surface. The overexpressed LPA1 with a C-terminal V5 tag (LPA1-V5) is majorly expressed on the cell surface, while two deletion mutants (C320 and ∆84-87) failed to be trafficked to the cell surface. Further, site-directed mutagenesis analysis of the LPA1 revealed that Ile325, Tyr85, and Leu87 within these two fragments regulate LPA1 maturation and trafficking to the cell surface. Over-expression of Sar1, a component of coat protein complex II (COPII), enhances glycosylation of LPA1 wild type, but not these mutants. The mutants of LPA1 are majorly localized in the endoplasmic reticulum (ER) and exhibit a higher binding affinity to heat shock protein 70 (Hsp70), when compared to the LPA1 wild type. Further, we found that all these mutants failed to increase phosphorylation of Erk, and the cytokine release in response to LPA treatment. These results suggest that Ile325, Tyr85, and Leu87 within LPA1 are essential for LPA1 protein properly folding in the ER.
Antonio Mazzocca - One of the best experts on this subject based on the ideXlab platform.
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Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth.
ChemMedChem, 2021Co-Authors: Davide Gnocchi, Carlo Sabbà, Maria M Cavalluzzi, Giuseppe F Mangiatordi, Rosanna Rizzi, Cosimo Tortorella, Mauro Spennacchio, Giovanni Lentini, Angela Altomare, Antonio MazzoccaAbstract:Despite the increasing incidence of Hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that Lysophosphatidic Acid Receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic Acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic Acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic Acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic Acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic Acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.
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Novel Lysophosphatidic Acid Receptor 6 antagonists inhibit hepatocellular carcinoma growth through affecting mitochondrial function
Journal of Molecular Medicine, 2020Co-Authors: Davide Gnocchi, Carlo Sabbà, Maria M Cavalluzzi, Giovanni Lentini, Saketh Kapoor, Patrizia Nitti, Nunzio Denora, Antonio MazzoccaAbstract:Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the commonest liver cancer. It is expected to become the third leading cause of cancer-related deaths in Western countries by 2030. Effective pharmacological approaches for HCC are still unavailable, and the currently approved systemic treatments are unsatisfactory in terms of therapeutic results, showing many side effects. Thus, searching for new effective and nontoxic molecules for HCC treatment is of paramount importance. We previously demonstrated that Lysophosphatidic Acid (LPA) is an important contributor to the pathogenesis of HCC and that Lysophosphatidic Acid Receptor 6 (LPAR6) actively supports HCC tumorigenicity. Here, we screened for novel LPAR6 antagonists and found that two compounds, 4-methylene-2-octyl-5-oxotetra-hydrofuran-3-carboxylic Acid (C75) and 9-xanthenylacetic Acid (XAA), efficiently inhibit HCC growth, both in vitro and in vitro, without displaying toxic effects at the effective doses. We further investigated the mechanisms of action of C75 and XAA and found that these compounds determine a G1-phase cell cycle arrest, without inducing apoptosis at the effective doses. Moreover, we discovered that both molecules act on mitochondrial homeostasis, by increasing mitochondrial biogenesis and reducing mitochondrial membrane potential. Overall, our results show two newly identified LPAR6 antagonists with a concrete potential to be translated into effective and side effect–free molecules for HCC therapy.
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Lysophosphatidic Acid Receptor LPAR6 Supports the Tumorigenicity of Hepatocellular Carcinoma
Cancer research, 2015Co-Authors: Antonio Mazzocca, Francesco Dituri, Flavia De Santis, Addolorata Filannino, Chiara Lopane, Regina C. Betz, Naofumi Mukaida, Peter Winter, Cosimo TortorellaAbstract:The aberrant processes driving hepatocellular carcinoma (HCC) are not fully understood. Lysophosphatidic Acid Receptors (LPAR) are commonly overexpressed in HCC, but their contributions to malignant development are not well established. In this report, we show that aberrant expression of LPAR6 sustains tumorigenesis and growth of HCC. Overexpression of LPAR6 in HCC specimens associated with poor survival in a cohort of 128 patients with HCC. We took a genetic approach to elucidate how LPAR6 sustains the HCC tumorigenic process, including through an expression profiling analysis to identify genes under the control of LPAR6. RNAi-mediated attenuation of LPAR6 impaired HCC tumorigenicity in tumor xenograft assays. Expression profiling and mechanistic analyses identified Pim-3 as a pathophysiologically relevant LPAR6 target gene. In nonmalignant cells where LPAR6 overexpression was sufficient to drive malignant character, Pim-3 was upregulated at the level of transcription initiation through a STAT3-dependent mechanism. A further analysis of HCC clinical specimens validated the connection between overexpression of LPAR6 and Pim-3, high proliferation rates, and poorer survival outcomes. Together, our findings establish LPAR6 as an important theranostic target in HCC tumorigenesis. Cancer Res; 75(3); 532–43. ©2014 AACR .
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1044 Lysophosphatidic Acid Receptor 6 (LPA6) PROMOTES HEPATOCELLULAR CARCINOMA GROWTH AND PROGRESSION THROUGH ACTIVATION OF PIM-3 PROTO-ONCOGENE KINASE
Journal of Hepatology, 2013Co-Authors: Antonio Mazzocca, Francesco Dituri, F. De Santis, Luigi Lupo, A. Azzariti, Carlo Sabbà, Gianluigi GiannelliAbstract:1044 Lysophosphatidic Acid Receptor 6 (LPA6) PROMOTES HEPATOCELLULAR CARCINOMA GROWTH AND PROGRESSION THROUGH ACTIVATION OF PIM-3 PROTO-ONCOGENE KINASE A. Mazzocca, F. Dituri, F. De Santis, L. Lupo, A. Azzariti, C. Sabba, G. Giannelli. Internal Medicine Unit C. ‘Frugoni’ University of Bari A. Moro, Section of General Surgery and Organ Transplantation, University of Bari Medical School, Department of Experimental Oncology, National Cancer Institute, Bari, Italy E-mail: gianluigi.giannelli@uniba.it
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276 Lysophosphatidic Acid Receptor 6 (LPA6) IS A MASTER REGULATOR ORCHESTRATING AND PROMOTING TUMOR GROWTH DURING HCC PROGRESSION
Journal of Hepatology, 2012Co-Authors: Antonio Mazzocca, Francesco Dituri, F. De Santis, Salvatore Antonaci, Gianluigi GiannelliAbstract:276 Lysophosphatidic Acid Receptor 6 (LPA6) IS A MASTER REGULATOR ORCHESTRATING AND PROMOTING TUMOR GROWTH DURING HCC PROGRESSION A. Mazzocca, F. Dituri, F. De Santis, S. Antonaci, G. Giannelli. Department of Emergency and Organ Transplantation, Section of Internal Medicine Allergology and Immunology, Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari, Bari, Italy E-mail: g.giannelli@intmed.uniba.it
Toshifumi Tsujiuchi - One of the best experts on this subject based on the ideXlab platform.
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Comparative analyses of Lysophosphatidic Acid Receptor-mediated signaling
Cellular and Molecular Life Sciences, 2015Co-Authors: Nobuyuki Fukushima, Shoichi Ishii, Toshifumi Tsujiuchi, Nao Kagawa, Kazutaka KatohAbstract:Lysophosphatidic Acid (LPA) is a bioactive lipid mediator that activates G protein-coupled LPA Receptors to exert fundamental cellular functions. Six LPA Receptor genes have been identified in vertebrates and are classified into two subfamilies, the endothelial differentiation genes (edg) and the non-edg family. Studies using genetically engineered mice, frogs, and zebrafish have demonstrated that LPA Receptor-mediated signaling has biological, developmental, and pathophysiological functions. Computational analyses have also identified several amino Acids (aa) critical for LPA recognition by human LPA Receptors. This review focuses on the evolutionary aspects of LPA Receptor-mediated signaling by comparing the aa sequences of vertebrate LPA Receptors and LPA-producing enzymes; it also summarizes the LPA Receptor-dependent effects commonly observed in mouse, frog, and fish.
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Abstract 3775: Lysophosphatidic Acid Receptor-3 pathways are involved in up-regulation of cell migration and invasion activity of human sarcoma cells.
Tumor Biology, 2013Co-Authors: Kanya Honoki, Hiromasa Tsujiuchi, Akira Kido, Shinji Tsukamoto, Yasuhito Tanaka, Toshifumi TsujiuchiAbstract:Lysophosphatidic Acid (LPA) acts through G-protein coupled transmembrane Receptors, and at least 6 types of LPA Receptors (LPARs) have been identified. They regulate many different cellular responses, such as proliferation, survival, differentiation, migration, cytoskeletal changes and calcium influx through these pathways, and may act as a positive or negative regulator of cancer cell behaviors in a Receptor specific manner which depends on cell types. Gene expression profiles analyzed in rat sarcoma model showed highly metastatic osteosarcoma cells expressing abundant LPA Receptor-3 (LPAR3) compared to mesenchymal stem cells and non-metastatic MFH cells. In the current study, we generated LPAR3-knockdown cells from human fibrosarcoma HT1080 and osteosarcoma HOS cells by transfection with shRNA plasmids and investigated the involvement of LPA3 pathway for cell migration and invasion abilities. Both sarcoma cells expressed through LPAR1 to 5 except for LPAR1 in osteosarcoma HOS. Firstly, we tested the effects of chemical inhibitors of downstream effector of G-proteins, and results suggested that downstream of Gi and Gq protein inhibition suppressed cell motility in both sarcoma cells, while downstream of G12/13 inhibition did not. Then, we generated LPAR3 knockdown cells by transfection of shRNA for LPAR3, which resulted in effective knockdown of the LPAR3 expression in those cells. Expression of autotaxin, a mediator for LPA production, was suppressed in HT1080 but not in HOS by shRNA, indicating the difference of LPA production loop between those cells. LPAR3 knockdown did not affect cellular growth rates in both sarcoma cells. Moreover, LPA treatments stimulated cell proliferation in a dose dependent manner even in LPAR-3 knockdown cells, suggesting that LPA signaling on cell proliferation could be regulated by other LPAR pathways rather than LPAR3 in these cells. On the contrary, LPAR3-knockdown cells showed significantly lower cell motility than control cells both in cell motility assay and in scrape assay. Invasion assay with the Matrigel-coated filter also showed significantly lower invasion activities in LPAR3-knockdown HT1080 cells, which originally showed strong invasive capacity. While, there were no differences observed in matrix metalloproteinase (MMP) -2 and 9 activities on gelatin zymography, suggesting that the control of invasiveness through LPAR3 signaling pathways was independently regulated from MMPs. These results suggest that a part of the abilities for cell migration and invasion in human sarcoma cells were possibly regulated through the downstream of LPAR3, Gi and Gq protein signaling pathways, and those pathways could be the candidates for molecular targeted therapy against sarcomas. Further elucidation of detailed mechanisms underlying in these complex pathways will be required for future therapeutic approach. Citation Format: Kanya Honoki, Hiromasa Tsujiuchi, Akira Kido, Shinji Tsukamoto, Yasuhito Tanaka, Toshifumi Tsujiuchi. Lysophosphatidic Acid Receptor-3 pathways are involved in up-regulation of cell migration and invasion activity of human sarcoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3775. doi:10.1158/1538-7445.AM2013-3775
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Lysophosphatidic Acid Receptor 3 increases tumorigenicity and aggressiveness of rat hepatoma rh7777 cells
Molecular Carcinogenesis, 2013Co-Authors: Kyoko Okabe, Nobuyuki Fukushima, Kanya Honoki, Mai Hayashi, Kohei Kato, Mai Okumura, Rie Fukui, Toshifumi TsujiuchiAbstract:Lysophosphatidic Acid (LPA), which interacts with G protein-coupled transmembrane LPA Receptors exhibits several biological effects, such as cell proliferation, migration, and differentiation. Recently, it has been reported that alteration of LPA Receptor genes occurs in several cancer cells. In this study, to assess the biological role of LPA Receptor-3 (LPA3) in the pathogenesis of tumor cells, we generated the Lpar3-expressing cells (RHa3B12 and RHa3G8) from rat hepatoma RH7777 cells, and examined their abilities of cell migration and tumorigenicity, compared with the Lpar3-unexpressing cells. In cell motility and invasion assays, RHa3B12 and RHa3G8 cells showed significantly higher intrinsic activity without LPA treatment than control RH7777AB cells. LPA treatment further increased cell motility and invasion of these cells. The cell motility of RHa3B12 and RHa3G8 cells stimulated by LPA treatment was significantly suppressed by pretreatment with inhibitors of Gi or Gq proteins. In a soft agar assay, the large sized colonies were formed in RHa3B12 and RHa3G8 cells, but not in RH7777AB cells. The cell survival of RHa3G8 cells treated with cisplatin (CDDP) or doxorubicin (DOX) was higher than that of RH7777AB cells, correlating with the elevated expression levels of multidrug-resistance related genes, Mdr1a, Mdr1b, and Gstp1. These results suggest that LPA3 may be involved in progression and aggressiveness of rat hepatoma RH7777 cells. © 2011 Wiley Periodicals, Inc.
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Mutations of Lysophosphatidic Acid Receptor Genes in Human Osteosarcoma Cells
Pathobiology : journal of immunopathology molecular and cellular biology, 2010Co-Authors: Kyoko Okabe, Nobuyuki Fukushima, Kanya Honoki, Toshio Mori, Mai Hayashi, Minako Fujii, Toshifumi TsujiuchiAbstract:Objective: Lysophosphatidic Acid (LPA), which is a bioactive phospholipid, interacts with specific G protein-coupled transmembrane Receptors. Recently, alterations in LPA Receptor g
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Infrequent mutation of Lysophosphatidic Acid Receptor-1 gene in hamster pancreatic duct adenocarcinomas and established cell lines.
Journal of toxicologic pathology, 2009Co-Authors: Toshifumi Tsujiuchi, Yumi Obo, Mami Furukawa, Mayuko Hotta, Ayako Yamasaki, Kanya Honoki, Chie Kusunoki, Naoko Suyama, Toshio Mori, Nobuyuki FukushimaAbstract:To evaluate the involvement of Lysophosphatidic Acid Receptor-1 (LPA1) gene alteration in pancreatic carcinogenesis, we investigated mutations in the LPA1 gene in hamster pancreatic duct adenocarcinomas (PDAs) and established cell lines. Female Syrian golden hamsters received 30 mg/kg of N-nitrosobis(2-oxopropyl)amine (BOP) followed by repeated exposure to an augmentation pressure regimen consisting of a choline-deficient diet combined with DL-ethionine and then L-methionine and a further administration of 20 mg/kg BOP. A total of 10 PDAs obtained 10 weeks after beginning the experiment and three cell lines established from subcutaneously transplantable PDAs in syngeneic hamsters were examined for mutations using reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) analysis. A mutation was detected in only one PDA (1/10, 10%) in the form of a GGA to GTA (Gly to Val) transversion at codon 355, and no mutations were detected in the three cell lines. These results suggest that the LPA1 gene mutation may play roles in a limited fraction of BOP-induced pancreatic duct carcinogenesis in hamsters.
