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Lysophosphatidic Acid Signaling in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 May 2024 | Viewed by 7248

Special Issue Editors


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Guest Editor
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Interests: mitochondria; premature aging; DNA-PKcs; MOMP; lysophosphatidic acid; DNA repair

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Guest Editor
Department of Life Science, National Taiwan University, Taipei 10617, Taiwan
Interests: cancer biology; angiogenesis; lysophosphatidic acid; lysophosphatidic acid receptors; aryl hydrocarbon receptor; cell aging; bioengineering
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Special Issue Information

Dear Colleagues,

Lysophosphatidic acid (LPA) is a small phospholipid acting as an extracellular lipid-controlling hormone. LPA mediates cellular apoptosis, invasion, and migration by activating its six G protein-coupled receptors (LPARs). LPA and LPARs mediate a broad range of biological effects in many tissue types. An abnormal level of LPA or LPARs has been shown to impair development and individual healthiness. For instance, LPA and LPARs have diverse effects on the development of the nervous system and cardiovascular system. In addition, LPA signaling has been suggested to be a potent signaling pathway with wide-ranging effects on the aging process. Besides, high levels of LPA are found in the tumor microenvironment. LPA has been suggested as an essential factor for the survival and growth of cancer cells. However, the roles of LPA in antitumor therapy remain vastly unexplored. Taken together, this Special Issue aims to update the current understandings about the roles of LPA and LPARs in human health and diseases.

Dr. Wei-Min Chen
Prof. Dr. Hsinyu Lee
Guest Editors

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Published Papers (6 papers)

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Research

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13 pages, 2072 KiB  
Article
Lysophosphatidic Acid Receptor 3 Activation Is Involved in the Regulation of Ferroptosis
by Yi-Xun Huang, Kuan-Hung Lin, Jui-Chung Chiang, Wei-Min Chen and Hsinyu Lee
Int. J. Mol. Sci. 2024, 25(4), 2315; https://doi.org/10.3390/ijms25042315 - 15 Feb 2024
Viewed by 940
Abstract
Ferroptosis, a unique form of programmed cell death trigged by lipid peroxidation and iron accumulation, has been implicated in embryonic erythropoiesis and aging. Our previous research demonstrated that lysophosphatidic acid receptor 3 (LPA3) activation mitigated oxidative stress in progeria cells and [...] Read more.
Ferroptosis, a unique form of programmed cell death trigged by lipid peroxidation and iron accumulation, has been implicated in embryonic erythropoiesis and aging. Our previous research demonstrated that lysophosphatidic acid receptor 3 (LPA3) activation mitigated oxidative stress in progeria cells and accelerated the recovery of acute anemia in mice. Given that both processes involve iron metabolism, we hypothesized that LPA3 activation might mediate cellular ferroptosis. In this study, we used an LPA3 agonist, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate (OMPT), to activate LPA3 and examine its effects on the ferroptosis process. OMPT treatment elevated anti-ferroptosis gene protein expression, including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), and ferritin heavy chain (FTH1), in erastin-induced cells. Furthermore, OMPT reduced lipid peroxidation and intracellular ferrous iron accumulation, as evidenced by C11 BODIPY™ 581/591 Lipid Peroxidation Sensor and FerroOrange staining. These observations were validated by applying LPAR3 siRNA in the experiments mentioned above. In addition, the protein expression level of nuclear factor erythroid 2-related factor (NRF2), a key regulator of oxidative stress, was also enhanced in OMPT-treated cells. Lastly, we verified that LPA3 plays a critical role in erastin-induced ferroptotic human erythroleukemia K562 cells. OMPT rescued the erythropoiesis defect caused by erastin in K562 cells based on a Gly A promoter luciferase assay. Taken together, our findings suggest that LPA3 activation inhibits cell ferroptosis by suppressing lipid oxidation and iron accumulation, indicating that ferroptosis could potentially serve as a link among LPA3, erythropoiesis, and aging. Full article
(This article belongs to the Special Issue Lysophosphatidic Acid Signaling in Health and Disease)
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17 pages, 3694 KiB  
Article
Global Proteomics Analysis of Lysophosphatidic Acid Signaling in PC-3 Human Prostate Cancer Cells: Role of CCN1
by Pravita Balijepalli, Guihua Yue, Bhagwat Prasad and Kathryn E. Meier
Int. J. Mol. Sci. 2024, 25(4), 2067; https://doi.org/10.3390/ijms25042067 - 08 Feb 2024
Cited by 1 | Viewed by 696
Abstract
Cysteine-rich angiogenic factor 61 (CCN1/Cyr61) is a matricellular protein that is induced and secreted in response to growth factors. Our previous work showed that 18:1-lysophosphatidic acid (LPA), which activates the G protein-coupled receptor LPAR1, induces CCN1 between 2–4 h in PC-3 human prostate [...] Read more.
Cysteine-rich angiogenic factor 61 (CCN1/Cyr61) is a matricellular protein that is induced and secreted in response to growth factors. Our previous work showed that 18:1-lysophosphatidic acid (LPA), which activates the G protein-coupled receptor LPAR1, induces CCN1 between 2–4 h in PC-3 human prostate cancer cells in a manner than enhances cell-substrate adhesion. While the time course of induction suggests that CCN1 contributes to intermediate events in LPA action, the roles of CCN1 in LPA-mediated signal transduction have not been fully elucidated. This study utilized a comprehensive global proteomics approach to identify proteins up- or down-regulated in response to treatment of PC-3 cells with LPA for three hours, during the time of peak CCN1 levels. In addition, the effects of siRNA-mediated CCN1 knockdown on LPA responses were analyzed. The results show that, in addition to CCN1, LPA increased the levels of multiple proteins. Proteins up-regulated by LPA included metastasis-associated in colon cancer protein 1 (MACC1) and thrombospondin-1 (TSP1/THBS1); both MACC1 and TSP1 regulated cancer cell adhesion and motility. LPA down-regulated thioredoxin interacting protein (TXNIP). CCN1 knockdown suppressed the LPA-induced up-regulation of 30 proteins; these included MACC1 and TSP1, as confirmed by immunoblotting. Gene ontology and STRING analyses revealed multiple pathways impacted by LPA and CCN1. These results indicate that CCN1 contributes to LPA signaling cascades that occur during the intermediate phase after the initial stimulus. The study provides a rationale for the development of interventions to disrupt the LPA-CCN1 axis. Full article
(This article belongs to the Special Issue Lysophosphatidic Acid Signaling in Health and Disease)
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9 pages, 2073 KiB  
Article
Neurological Improvement via Lysophosphatidic Acid Administration in a Rodent Model of Cardiac Arrest-Induced Brain Injury
by Mitsuaki Nishikimi, Rishabh C. Choudhary, Muhammad Shoaib, Tsukasa Yagi, Lance B. Becker and Junhwan Kim
Int. J. Mol. Sci. 2023, 24(24), 17451; https://doi.org/10.3390/ijms242417451 - 14 Dec 2023
Viewed by 692
Abstract
Lysophosphatidic acid (LPA) serves as a fundamental constituent of phospholipids. While prior studies have shown detrimental effects of LPA in a range of pathological conditions, including brain ischemia, no studies have explored the impact of LPA in the context of cardiac arrest (CA). [...] Read more.
Lysophosphatidic acid (LPA) serves as a fundamental constituent of phospholipids. While prior studies have shown detrimental effects of LPA in a range of pathological conditions, including brain ischemia, no studies have explored the impact of LPA in the context of cardiac arrest (CA). The aim of this study is to evaluate the effects of the intravenous administration of an LPA species containing oleic acid, LPA (18:1) on the neurological function of rats (male, Sprague Dawley) following 8 min of asphyxial CA. Baseline characteristics, including body weight, surgical procedure time, and vital signs before cardiac arrest, were similar between LPA (18:1)-treated (n = 10) and vehicle-treated (n = 10) groups. There was no statistically significant difference in 24 h survival between the two groups. However, LPA (18:1)-treated rats exhibited significantly improved neurological function at 24 h examination (LPA (18:1), 85.4% ± 3.1 vs. vehicle, 74.0% ± 3.3, p = 0.045). This difference was most apparent in the retention of coordination ability in the LPA (18:1) group (LPA (18:1), 71.9% ± 7.4 vs. vehicle, 25.0% ± 9.1, p < 0.001). Overall, LPA (18:1) administration in post-cardiac arrest rats significantly improved neurological function, especially coordination ability at 24 h after cardiac arrest. LPA (18:1) has the potential to serve as a novel therapeutic in cardiac arrest. Full article
(This article belongs to the Special Issue Lysophosphatidic Acid Signaling in Health and Disease)
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19 pages, 1180 KiB  
Article
Plasma Lysophosphatidic Acid Concentrations in Sex Differences and Psychiatric Comorbidity in Patients with Cocaine Use Disorder
by Nerea Requena-Ocaña, María Flores-López, Nuria García-Marchena, Francisco J. Pavón-Morón, Carmen Pedraza, Agustín Wallace, Estela Castilla-Ortega, Fernando Rodríguez de Fonseca, Antonia Serrano and Pedro Araos
Int. J. Mol. Sci. 2023, 24(21), 15586; https://doi.org/10.3390/ijms242115586 - 25 Oct 2023
Viewed by 1026
Abstract
We have recently reported sex differences in the plasma concentrations of lysophosphatidic acid (LPA) and alterations in LPA species in patients with alcohol and cocaine use disorders. Preclinical evidence suggests a main role of lysophosphatidic acid (LPA) signaling in anxiogenic responses and drug [...] Read more.
We have recently reported sex differences in the plasma concentrations of lysophosphatidic acid (LPA) and alterations in LPA species in patients with alcohol and cocaine use disorders. Preclinical evidence suggests a main role of lysophosphatidic acid (LPA) signaling in anxiogenic responses and drug addiction. To further explore the potential role of the LPA signaling system in sex differences and psychiatric comorbidity in cocaine use disorder (CUD), we conducted a cross-sectional study with 88 patients diagnosed with CUD in outpatient treatment and 60 healthy controls. Plasma concentrations of total LPA and LPA species (16:0, 18:0, 18:1, 18:2 and 20:4) were quantified and correlated with cortisol and tryptophan metabolites [tryptophan (TRP), serotonin (5-HT), kynurenine (KYN), quinolinic acid (QUIN) and kynurenic acid (KYNA)]. We found sexual dimorphism for the total LPA and most LPA species in the control and CUD groups. The total LPA and LPA species were not altered in CUD patients compared to the controls. There was a significant correlation between 18:2 LPA and age at CUD diagnosis (years) in the total sample, but total LPA, 16:0 LPA and 18:2 LPA correlated with age at onset of CUD in male patients. Women with CUD had more comorbid anxiety and eating disorders, whereas men had more cannabis use disorders. Total LPA, 18:0 LPA and 20:4 LPA were significantly decreased in CUD patients with anxiety disorders. Both 20:4 LPA and total LPA were significantly higher in women without anxiety disorders compared to men with and without anxiety disorders. Total LPA and 16:0 LPA were significantly decreased in CUD patients with childhood ADHD. Both 18:1 LPA and 20:4 LPA were significantly augmented in CUD patients with personality disorders. KYNA significantly correlated with total LPA, 16:0 LPA and 18:2 LPA species, while TRP correlated with the 18:1 LPA species. Our results demonstrate that LPA signaling is affected by sex and psychiatric comorbidity in CUD patients, playing an essential role in mediating their anxiety symptoms. Full article
(This article belongs to the Special Issue Lysophosphatidic Acid Signaling in Health and Disease)
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19 pages, 16999 KiB  
Article
Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression
by Matthew G. K. Benesch, Rongrong Wu, Xiaoyun Tang, David N. Brindley, Takashi Ishikawa and Kazuaki Takabe
Int. J. Mol. Sci. 2023, 24(12), 9812; https://doi.org/10.3390/ijms24129812 - 06 Jun 2023
Cited by 3 | Viewed by 1715
Abstract
Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are [...] Read more.
Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy. Full article
(This article belongs to the Special Issue Lysophosphatidic Acid Signaling in Health and Disease)
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19 pages, 1563 KiB  
Review
Entering, Linked with the Sphinx: Lysophosphatidic Acids Everywhere, All at Once, in the Oral System and Cancer
by D. Roselyn Cerutis, Michael D. Weston and Takanari Miyamoto
Int. J. Mol. Sci. 2023, 24(12), 10278; https://doi.org/10.3390/ijms241210278 - 17 Jun 2023
Viewed by 1259
Abstract
Oral health is crucial to overall health, and periodontal disease (PDD) is a chronic inflammatory disease. Over the past decade, PDD has been recognized as a significant contributor to systemic inflammation. Here, we relate our seminal work defining the role of lysophosphatidic acid [...] Read more.
Oral health is crucial to overall health, and periodontal disease (PDD) is a chronic inflammatory disease. Over the past decade, PDD has been recognized as a significant contributor to systemic inflammation. Here, we relate our seminal work defining the role of lysophosphatidic acid (LPA) and its receptors (LPARs) in the oral system with findings and parallels relevant to cancer. We discuss the largely unexplored fine-tuning potential of LPA species for biological control of complex immune responses and suggest approaches for the areas where we believe more research should be undertaken to advance our understanding of signaling at the level of the cellular microenvironment in biological processes where LPA is a key player so we can better treat diseases such as PDD, cancer, and emerging diseases. Full article
(This article belongs to the Special Issue Lysophosphatidic Acid Signaling in Health and Disease)
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