scholarly journals Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1629
Author(s):  
Yu-Hsuan Lin ◽  
Yueh-Chien Lin ◽  
Chien-Chin Chen
Keyword(s):  
Cancer Progression ◽  
Lysophosphatidic Acid ◽  
Lipid Mediator ◽  
Membrane Phospholipids ◽  
Receptor Antagonists ◽  
Preclinical Trial ◽  
Lpa Receptor ◽  
Cellular Effects ◽  
Lpa Receptors ◽  
And Function

Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.

Transcriptional regulation of lysophosphatidic acid receptors 2 and 3 regulates myeloid commitment of hematopoietic stem cells

2021 ◽  
Author(s):  
Kuan-Hung Lin ◽  
Jui-Chung Chiang ◽  
Wei-Min Chen ◽  
Ya-Hsuan Ho ◽  
Chao-Ling Yao ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Stem Cell Differentiation ◽  
Receptor Subtypes ◽  
Physical Interaction ◽  
Hematopoietic Stem ◽  
Lpa Receptor ◽  
Gata Factors ◽  
Lpa Receptors ◽  
Myeloid Progenitors

Lysophosphatidic acid (LPA) is one of the lipids identified to be involved in stem cell differentiation. It exerts various functions through activation of G protein-coupled LPA receptors (LPARs). In previous studies, we have demonstrated that activation of LPA receptor 3 (LPA3) promotes erythropoiesis in human HSCs and zebrafish using molecular andpharmacological approaches. Our results show that treatment of LPA2 agonist suppressed erythropoiesis, whereas activation of LPA3 by 2S-OMPT promoted it, both in vitro and in vivo. Furthermore, we have demonstrated the inhibitory role of LPA3 during megakaryopoiesis. However, the mechanism underlying these observation remains elusive. In the present study, we suggest that the expression pattern of LPARs may be correlated with the transcriptional factors GATA-1 and GATA-2 at different stages of myeloid progenitors. We determined that manipulation of GATA factors affected the expression levels of LPA2 and LPA3. Using luciferase assays, we demonstrate that the promoter regions of LPAR2 and LPAR3 were regulated by these GATA factors. Mutation of GATA binding sites in these regions abrogated luciferase activity, suggesting that LPA2 and LPA3 are regulated by GATA factors. Moreover, physical interaction between GATA factors and the promoter region of LPA receptors was verified using chromatin immunoprecipitation (ChIP) studies. Taken together, our results suggest that balance between LPA2 and LPA3, which may be determined by GATA factors, is a regulatory switch for lineage commitment in myeloid progenitors. The expression-level balance of LPA receptor subtypes represents a novel mechanism regulating erythropoiesis and megakaryopoiesis.

scholarly journals Dual Regulation of Actin Rearrangement through Lysophosphatidic Acid Receptor in Neuroblast Cell Lines: Actin Depolymerization by Ca2+-α-Actinin and Polymerization by Rho

2002 ◽  
Vol 13 (8) ◽  
pp. 2692-2705 ◽  
Author(s):  
Nobuyuki Fukushima ◽  
Isao Ishii ◽  
Yoshiaki Habara ◽  
Cara B. Allen ◽  
Jerold Chun
Keyword(s):  
Lysophosphatidic Acid ◽  
Actin Polymerization ◽  
Rho Gtpase ◽  
Morphological Changes ◽  
Neuronal Morphology ◽  
Single Type ◽  
Lipid Mediator ◽  
Lpa Receptor ◽  
Actin Depolymerization ◽  
Actin Rearrangement

Lysophosphatidic acid (LPA) is a potent lipid mediator with actions on many cell types. Morphological changes involving actin polymerization are mediated by at least two cognate G protein-coupled receptors, LPA1/EDG-2 or LPA2/EDG-4. Herein, we show that LPA can also induce actin depolymerization preceding actin polymerization within single TR mouse immortalized neuroblasts. Actin depolymerization resulted in immediate loss of membrane ruffling, whereas actin polymerization resulted in process retraction. Each pathway was found to be independent: depolymerization mediated by intracellular calcium mobilization, and α-actinin activity and polymerization mediated by the activation of the small Rho GTPase. α-Actinin–mediated depolymerization seems to be involved in growth cone collapse of primary neurons, indicating a physiological significance of LPA-induced actin depolymerization. Further evidence for dual regulation of actin rearrangement was found by heterologous retroviral transduction of either lpa 1 orlpa 2 in B103 cells that neither express LPA receptors nor respond to LPA, to confer both forms of LPA-induced actin rearrangements. These results suggest that diverging intracellular signals from a single type of LPA receptor could regulate actin depolymerization, as well as polymerization, within a single cell. This dual actin rearrangement may play a novel, important role in regulation of the neuronal morphology and motility during brain development.

scholarly journals Lysophosphatidic acid receptor 1 modulates lipopolysaccharide-induced inflammation in alveolar epithelial cells and murine lungs

2011 ◽  
Vol 301 (4) ◽  
pp. L547-L556 ◽  
Author(s):  
Jing Zhao ◽  
Donghong He ◽  
Yanlin Su ◽  
Evgeny Berdyshev ◽  
Jerold Chun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lysophosphatidic Acid ◽  
Lung Inflammation ◽  
Lung Epithelial Cells ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Wild Type ◽  
Lpa Receptor ◽  
Knock Down ◽  
Lpa Receptors

Lysophosphatidic acid (LPA), a bioactive phospholipid, plays an important role in lung inflammation by inducing the release of chemokines and lipid mediators. Our previous studies have shown that LPA induces the secretion of interleukin-8 and prostaglandin E2 in lung epithelial cells. Here, we demonstrate that LPA receptors contribute to lipopolysaccharide (LPS)-induced inflammation. Pretreatment with LPA receptor antagonist Ki16425 or downregulation of LPA receptor 1 (LPA1) by small-interfering RNA (siRNA) attenuated LPS-induced phosphorylation of p38 MAPK, I-κB kinase, and I-κB in MLE12 epithelial cells. In addition, the blocking of LPA1 also suppressed LPS-induced IL-6 production. Furthermore, LPS treatment promoted interaction between LPA1 and CD14, a LPS coreceptor, in a time- and dose-dependent manner. Disruption of lipid rafts attenuated the interaction between LPA1 and CD14. Mice challenged with LPS increased plasma LPA levels and enhanced expression of LPA receptors in lung tissues. To further investigate the role of LPA receptors in LPS-induced inflammation, wild-type, or LPA1-deficient mice, or wild-type mice pretreated with Ki16425 were intratracheally challenged with LPS for 24 h. Knock down or inhibition of LPA1 decreased LPS-induced IL-6 release in bronchoalveolar lavage (BAL) fluids and infiltration of cells into alveolar space compared with wild-type mice. However, no significant differences in total protein concentration in BAL fluids were observed. These results showed that knock down or inhibition of LPA1 offered significant protection against LPS-induced lung inflammation but not against pulmonary leak as observed in the murine model for lung injury.

Structure of ginseng major latex-like protein 151 and its proposed lysophosphatidic acid-binding mechanism

2015 ◽  
Vol 71 (5) ◽  
pp. 1039-1050 ◽  
Author(s):  
Sun-Hye Choi ◽  
Myoung-Ki Hong ◽  
Hyeon-Joong Kim ◽  
Nayeon Ryoo ◽  
Hyewhon Rhim ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Plasma Proteins ◽  
Site Directed Mutagenesis ◽  
Titration Calorimetry ◽  
Amino Acid Residues ◽  
Lpa Receptor ◽  
Biological Responses ◽  
Lpa Receptors ◽  
Intracellular Ca ◽  
G Protein Coupled

Lysophosphatidic acid (LPA) is a phospholipid growth factor with myriad effects on biological systems. LPA is usually present bound to animal plasma proteins such as albumin or gelsolin. When LPA complexes with plasma proteins, it binds to its cognate receptors with higher affinity than when it is free. Recently, gintonin from ginseng was found to bind to LPA and to activate mammalian LPA receptors. Gintonin contains two components: ginseng major latex-like protein 151 (GLP) and ginseng ribonuclease-like storage protein. Here, the crystal structure of GLP is reported, which belongs to the plant Bet v 1 superfamily, and a model is proposed for how GLP binds LPA. Amino-acid residues of GLP recognizing LPA were identified using site-directed mutagenesis and isothermal titration calorimetry. The resulting GLP mutants were used to study the activation of LPA receptor-dependent signalling pathways. In contrast to wild-type GLP, the H147A mutant did not bind LPA, elicit intracellular Ca2+transients in neuronal cells or activate Ca2+-dependent Cl−channels inXenopusoocytes. Based on these results, a mechanism by which GLP recognizes LPA and its requirement to activate G protein-coupled LPA receptors to elicit diverse biological responses were proposed.

Epidermal growth factor increases lysophosphatidic acid production in human ovarian cancer cells: roles for phospholipase D2 and receptor transactivation

2010 ◽  
Vol 298 (1) ◽  
pp. C163-C170 ◽  
Author(s):  
Ashley J. Snider ◽  
Zhihong Zhang ◽  
Yuhuan Xie ◽  
Kathryn E. Meier
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Lysophosphatidic Acid ◽  
Cross Talk ◽  
Human Ovarian Cancer ◽  
Lpa Receptor ◽  
Lpa Receptors ◽  
Epidermal Growth

Lysophosphatidic acid (LPA), is a lipid mediator that binds to G-protein coupled receptors. Epidermal growth factor (EGF), a polypeptide growth factor, binds to the EGF receptor (EGFR), a receptor tyrosine kinase. Both LPA and EGF induce responses in tumor cells that include proliferation, migration, metastasis, and induction of angiogenesis. LPA has the potential to act as an autocrine/paracrine factor and can transactivate the EGFR. This study explores the role of phospholipase D2 (PLD2) activation in LPA production, as well as cross-talk between EGF and LPA receptors. We demonstrate that EGF and LPA both stimulate production of LPA by OVCAR3 and SKOV3 human ovarian cancer cell lines. PD158780, an EGFR-selective tyrosine kinase inhibitor, blocks LPA production in response to both EGF and LPA in OVCAR3 and SKOV3 cells. Pertussis toxin, an inhibitor of LPA receptor signaling, inhibits LPA production in response to both EGF and LPA. Similar results were observed for the LPA receptor antagonist, Ki16425. Overexpression of PLD2 increases LPA production, while knockdown of PLD2 blocks EGF-induced LPA production. A phospholipase A2 (PLA2) inhibitor also blocks LPA- and EGF-induced LPA production. These results indicate that EGF stimulates LPA production in a manner that requires PLD2, and suggest that cross-talk can occur bidirectionally between EGF and LPA receptors.

scholarly journals Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Silvia Anahi Valdés-Rives ◽  
Aliesha González-Arenas
Keyword(s):  
Wound Healing ◽  
G Protein ◽  
Cancer Progression ◽  
Lysophosphatidic Acid ◽  
Therapeutic Target ◽  
G Protein Coupled Receptors ◽  
Cancer Development ◽  
Cellular Processes ◽  
Lpa Receptors ◽  
G Protein Coupled

Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA1–6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer-related inflammation and its impact on cancer progression.

scholarly journals Lysophosphatidic Acid–Induced EGFR Transactivation Promotes Gastric Cancer Cell DNA Replication by Stabilizing Geminin in the S Phase

2021 ◽  
Vol 12 ◽  
Author(s):  
Haile Zhao ◽  
Gezi Gezi ◽  
Xiaoxia Tian ◽  
Peijun Jia ◽  
Morigen Morigen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Progression ◽  
Lysophosphatidic Acid ◽  
Growth Factor Receptor ◽  
S Phase ◽  
Gastric Cancer Cells ◽  
Egfr Transactivation ◽  
Lpa Receptor ◽  
Multifunctional Protein

Geminin, an inhibitor of the DNA replication licensing factor, chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression, but the molecular details are largely unknown. Here, we found that lysophosphatidic acid (LPA)–induced upregulation of geminin was specific to gastric cancer cells. LPA acted via LPA receptor (LPAR) 3 and matrix metalloproteinases (MMPs) signaling to transactivate epidermal growth factor receptor (EGFR) (Y1173) and thereby stabilize geminin expression level during the S phase. LPA also induced the expression of deubiquitinating protein (DUB) 3, which prevented geminin degradation. These results reveal a novel mechanism underlying gastric cancer progression that involves the regulation of geminin stability by LPA-induced EGFR transactivation and provide potential targets for the signaling pathway and tumor cell–specific inhibitors.

Expression and function of lysophosphatidic acid in theca cells of the bovine ovarian follicle

2014 ◽  
Author(s):  
Emilia Sinderewicz ◽  
Dorota Boruszewska ◽  
Ilona Kowalczyk-Zieba ◽  
Joanna Staszkiewicz ◽  
Katarzyna Grycmacher ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Ovarian Follicle ◽  
Theca Cells ◽  
And Function

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals Expression and Function of C1orf132 Long-Noncoding RNA in Breast Cancer Cell Lines and Tissues

2021 ◽  
Vol 22 (13) ◽  
pp. 6768
Author(s):  
Afsaneh Malekzadeh Shafaroudi ◽  
Ali Sharifi-Zarchi ◽  
Saeid Rahmani ◽  
Nahid Nafissi ◽  
Seyed Javad Mowla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
Migration Assay ◽  
And Function ◽  
Distal Promoter

miR-29b2 and miR-29c play a suppressive role in breast cancer progression. C1orf132 (also named MIR29B2CHG) is the host gene for generating both microRNAs. However, the region also expresses longer transcripts with unknown functions. We employed bioinformatics and experimental approaches to decipher C1orf132 expression and function in breast cancer tissues. We also used the CRISPR/Cas9 technique to excise a predicted C1orf132 distal promoter and followed the behavior of the edited cells by real-time PCR, flow cytometry, migration assay, and RNA-seq techniques. We observed that C1orf132 long transcript is significantly downregulated in triple-negative breast cancer. We also identified a promoter for the longer transcripts of C1orf132 whose functionality was demonstrated by transfecting MCF7 cells with a C1orf132 promoter-GFP construct. Knocking-out the promoter by means of CRISPR/Cas9 revealed no alterations in the expression of the neighboring genes CD46 and CD34, while the expression of miR-29c was reduced by half. Furthermore, the promoter knockout elevated the migration ability of the edited cells. RNA sequencing revealed many up- and downregulated genes involved in various cellular pathways, including epithelial to mesenchymal transition and mammary gland development pathways. Altogether, we are reporting here the existence of an additional/distal promoter with an enhancer effect on miR-29 generation and an inhibitory effect on cell migration.

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