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https://www.readbyqxmd.com/read/29331665/blocking-lpa-dependent-signaling-increases-ovarian-cancer-cell-death-in-response-to-chemotherapy
#1
LeAnn C Rogers, Ryan R Davis, Naveen Said, Thomas Hollis, Larry W Daniel
The paradoxical role of reactive oxygen species in cell death versus cell survival establishes a delicate balance between chemotherapy efficacy and management of detrimental side effects. Normal proliferative signaling requires that cells remain inside a redox range that allows reversible protein oxidation to occur. Shifting the redox environment toward highly reducing or oxidizing states leads to cellular stress and cell death. Reactive oxygen species produced in response to Taxol and cisplatin treatment are necessary for effective cancer cell killing but the same ROS leads to damaging side effects in normal tissues...
January 4, 2018: Redox Biology
https://www.readbyqxmd.com/read/29329782/lpa-induced-migration-of-ovarian-cancer-cells-requires-activation-of-erm-proteins-via-lpa1-and-lpa2
#2
Jeongrak Park, Jin-Hyuck Jang, Seojin Oh, Minhye Kim, Changhoon Shin, Minseok Jeong, Kyun Heo, Jong Bae Park, Sang Ryong Kim, Yong-Seok Oh
Lysophosphatidic acid (LPA) has been implicated in the pathology of human ovarian cancer. This phospholipid elicits a wide range of cancer cell responses, such as proliferation, trans-differentiation, migration, and invasion, via various G-protein-coupled LPA receptors (LPARs). Here, we explored the cellular signaling pathway via which LPA induces migration of ovarian cancer cells. LPA induced robust phosphorylation of ezrin/radixin/moesin (ERM) proteins, which are membrane-cytoskeleton linkers, in the ovarian cancer cell line OVCAR-3...
January 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29328374/atx%C3%A2-lpa-axis-facilitates-estrogen%C3%A2-induced-endometrial-cancer-cell-proliferation-via-mapk-erk-signaling-pathway
#3
Guo Zhang, Yuan Cheng, Qi Zhang, Xiaoping Li, Jingwei Zhou, Jianliu Wang, Lihui Wei
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX is a crucial factor that facilitates cancer progression; however, the effect of ATX on endometrial cancer has not been explored. The aim of the present study was to investigate the role of ATX in the progression of endometrial cancer. The immunohistochemical results revealed higher protein expression levels of ATX and LPA receptors (LPA 1, 2 and 3) in human endometrial cancer tissue than in non‑carcinoma tissue...
January 8, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29321663/lpa-signaling-is-regulated-through-the-primary-cilium-a-novel-target-in-glioblastoma
#4
Yuriy V Loskutov, Caryn L Griffin, Kristina M Marinak, Andrey Bobko, Naira V Margaryan, Werner J Geldenhuys, Jann N Sarkaria, Elena N Pugacheva
The primary cilium is a ubiquitous organelle presented on most human cells. It is a crucial signaling hub for multiple pathways including growth factor and G-protein coupled receptors. Loss of primary cilia, observed in various cancers, has been shown to affect cell proliferation. Primary cilia formation is drastically decreased in glioblastoma (GBM), however, the role of cilia in normal astrocyte or glioblastoma proliferation has not been explored. Here, we report that loss of primary cilia in human astrocytes stimulates growth rate in a lysophosphatidic acid (LPA)-dependent manner...
January 11, 2018: Oncogene
https://www.readbyqxmd.com/read/29309788/involvement-of-lpa-receptor-5-in-the-enhancement-of-cell-motile-activity-by-phorbol-ester-and-anticancer-drug-treatments-in-melanoma-a375%C3%A2-cells
#5
Kaori Fukushima, Kaede Takahashi, Aya Kurokawa, Kaichi Ishimoto, Shiho Otagaki, Kanako Minami, Nobuyuki Fukushima, Kanya Honoki, Toshifumi Tsujiuchi
Lysophosphatidic acid (LPA) signaling through six subtypes of LPA receptors (LPA1 to LPA6) regulates a variety of biological responses in cancer cells. The aim of our study was to evaluate an involvement of LPA receptors in the activation of cell motility by phorbol ester and anticancer drug treatments in melanoma A375 cells. Cells were treated with 12-O-tetradecanoylphorbol- 13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu) for 3 days. The cell motile activity of TPA treated cells was significantly higher than that of PDBu treated cells, correlating with LPAR5 expression levels...
January 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29305605/role-of-the-autotaxin-lpa-pathway-in-dexamethasone-induced-fibrotic-responses-and-extracellular-matrix-production-in-human-trabecular-meshwork-cells
#6
Megumi Honjo, Nozomi Igarashi, Junko Nishida, Makoto Kurano, Yutaka Yatomi, Koji Igarashi, Kuniyuki Kano, Junken Aoki, Makoto Aihara
Purpose: Dexamethasone (Dex) regulates aqueous humor outflow by inducing reorganization of the cytoskeleton and extracellular matrix (ECM) production. Rho kinase (ROCK) has an important role in this process, but the upstream pathway leading to its activation remains elusive. The purpose of the study was to determine the role of autotaxin (ATX), an enzyme involved in the generation of lysophosphatidic acid (LPA), in the Dex-induced fibrotic response and ECM production in human trabecular meshwork (HTM) cells...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29278716/2-o-carba-oleoyl-cyclic-phosphatidic-acid-induces-glial-proliferation-through-the-activation-of-lysophosphatidic-acid-receptor
#7
Shingo Nakajima, Mari Gotoh, Keiko Fukasawa, Hiromu Murofushi, Kimiko Murakami-Murofushi
Lysophosphatidic acid (LPA) and cyclic phosphatidic acid (cPA) are one of the lipid mediators regulating cell proliferation and differentiation through the activation of LPA receptors. An LPA receptor-mediated signal is important for the development of the central nervous system, while it has been demonstrated that LPA caused microglial activation and astroglial dysfunction. Previously, we have reported that cPA and carba analog of cPA, 2-O-carba-cPA (2ccPA), protected neural damage caused by transient ischemia...
December 23, 2017: Brain Research
https://www.readbyqxmd.com/read/29259748/discovery-of-a-slow-tight-binding-lpa1-antagonist-ono-0300302-for-the-treatment-of-benign-prostatic-hyperplasia
#8
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Keisuke Hirai, Masaki Asada, Masahiro Ikura, Naoki Matsunaga, Hiroshi Saga, Koji Shinozaki, Naoko Karakawa, Yuka Takada, Masashi Minami, Hiromu Egashira, Yoshihiro Sugiura, Masanori Yamada, Shinji Nakade, Yoshikazu Takaoka
Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p...
December 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29258556/lysophosphatidic-acid-via-lpa-receptor-5-protein-kinase-d-dependent-pathways-induces-a-motile-and-pro-inflammatory-microglial-phenotype
#9
I Plastira, E Bernhart, M Goeritzer, T DeVaney, H Reicher, A Hammer, B Lohberger, A Wintersperger, B Zucol, W F Graier, D Kratky, E Malle, W Sattler
BACKGROUND: Extracellular lysophosphatidic acid (LPA) species transmit signals via six different G protein-coupled receptors (LPAR1-6) and are indispensible for brain development and function of the nervous system. However, under neuroinflammatory conditions or brain damage, LPA levels increase, thereby inducing signaling cascades that counteract brain function. We describe a critical role for 1-oleyl-2-hydroxy-sn-glycero-3-phosphate (termed "LPA" throughout our study) in mediating a motile and pro-inflammatory microglial phenotype via LPAR5 that couples to protein kinase D (PKD)-mediated pathways...
December 19, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29258184/lysophospholipid-related-diseases-and-ppar%C3%AE-signaling-pathway
#10
REVIEW
Tamotsu Tsukahara, Yoshikazu Matsuda, Hisao Haniu
The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as cardiovascular diseases. Lysophosphatidic acid (LPA) belongs to a family of lipid mediators. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and an intracellular nuclear hormone receptor. In addition, several enzymes that utilize LPA as a substrate or generate it as a product are under its regulatory control...
December 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29239275/activation-of-lysophosphatidic-acid-receptor-3-inhibits-megakaryopoiesis-in-human-hematopoietic-stem-cells-and-zebrafish
#11
Kuan-Hung Lin, Meng-Wei Li, Ya-Chi Chang, Yu-Nung Lin, Ya-Hsuan Ho, Wei-Chun Weng, Chang-Jen Huang, Bei-En Chang, Chao-Ling Yao, Hsinyu Lee
Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid that exists in the plasma and platelets. It exerts its functions through activation of various LPA receptors (LPARs), which belong to the family of G protein-coupled receptors (GPCRs). Activation of LPARs has important roles in stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation remains elusive. In our previous studies, we have suggested that LPA receptor 2 (LPA<sub>2</sub>) and LPA receptor 3 (LPA<sub>3</sub>) play opposing roles, and may act as a molecular switch during megakaryocytic differentiation in K562 cells...
December 14, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29236751/lysophosphatidic-acid-receptor-mrna-levels-in-heart-and-white-adipose-tissue-are-associated-with-obesity-in-mice-and-humans
#12
Amy Brown, Intekhab Hossain, Lester J Perez, Carine Nzirorera, Kathleen Tozer, Kenneth D'Souza, Purvi C Trivedi, Christie Aguiar, Alexandra M Yip, Jennifer Shea, Keith R Brunt, Jean-Francois Legare, Ansar Hassan, Thomas Pulinilkunnil, Petra C Kienesberger
BACKGROUND: Lysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear. OBJECTIVES: This study aimed to characterize the mRNA expression of LPA receptors (LPA1-6) in the murine and human myocardium and adipose tissue, and its regulation in response to obesity. METHODS: LPA receptor mRNA levels were determined by qPCR in i) heart ventricles, isolated cardiomyocytes, and perigonadal adipose tissue from chow or high fat-high sucrose (HFHS)-fed male C57BL/6 mice, ii) 3T3-L1 adipocytes and HL-1 cardiomyocytes under conditions mimicking gluco/lipotoxicity, and iii) human atrial and subcutaneous adipose tissue from non-obese, pre-obese, and obese cardiac surgery patients...
2017: PloS One
https://www.readbyqxmd.com/read/29217823/lysophosphatidic-acid-protects-against-acetaminophen-induced-acute-liver-injury
#13
Geon Ho Bae, Sung Kyun Lee, Hyung Sik Kim, Mingyu Lee, Ha Young Lee, Yoe-Sik Bae
We investigated the effect of lysophosphatidic acid (LPA) in experimental acetaminophen (APAP)-induced acute liver injury. LPA administration significantly reduced APAP-challenged acute liver injury, showing attenuated liver damage, liver cell death and aspartate aminotransferase and alanine aminotransferase levels. APAP overdose-induced mortality was also significantly decreased by LPA administration. Regarding the mechanism involved in LPA-induced protection against acute liver injury, LPA administration significantly increased the glutathione level, which was markedly decreased in APAP challenge-induced acute liver injury...
December 8, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29211497/the-rho-kinase-isoforms-rock1-and-rock2-each-contribute-to-the-development-of-experimental-pulmonary-fibrosis
#14
Rachel S Knipe, Clemens K Probst, David Lagares, Alicia Franklin, Jillian J Spinney, Patricia L Brazee, Paula Grasberger, Linlin Zhang, Katharine E Black, Norihiko Sakai, Barry S Shea, James K Liao, Benjamin D Medoff, Andrew M Tager
Pulmonary fibrosis is thought to result from dysregulated wound repair after repetitive lung injury. Many cellular responses to injury involve rearrangements of the actin cytoskeleton mediated by the two isoforms of the Rho-associated coiled coil forming protein kinase, ROCK1 and ROCK2. Additionally, profibrotic mediators such as transforming growth factor-beta (TGF-β), thrombin and lysophosphatidic acid (LPA) act through receptors that activate ROCK. Inhibition of ROCK activation may be a potent therapeutic strategy for human pulmonary fibrosis...
December 6, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29208511/identification-of-potent-lysophosphatidic-acid-receptor-5-lpa5-antagonists-as-potential-analgesic-agents
#15
Yuichiro Kawamoto, Ryushi Seo, Nobuhito Murai, Hideki Hiyama, Hiromasa Oka
Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities...
November 26, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29197066/characterisation-of-the-properties-of-a-selective-orally-bioavailable-autotaxin-inhibitor-in-preclinical-models-of-advanced-stages-of-liver-fibrosis
#16
Manuel Baader, Tom Bretschneider, Andre Broermann, Joerg F Rippmann, Birgit Stierstorfer, Christian A Kuttruff, Michael Mark
BACKGROUND AND PURPOSE: Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six G protein-coupled receptors expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis...
December 2, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29182028/altered-expression-of-lysophosphatidic-acid-receptors-in-association-with-the-synthesis-of-estrogens-and-androgens-in-type-1-endometrial-cancer-biology
#17
Tomasz Wasniewski, Izabela Woclawek-Potocka
To establish association between two main lysophosphatidic acid (LPA) receptors (LPAR2 and LPAR1) with the synthesis of estrogens and androgens in type-1 endometrial carcinoma (EC), we evaluated correlation of LPARs expression with expression of steroid 5 alpha-reductase 2 - aromatase (SRD5A2), or cytochrome P450 family 19 subfamily A member 1-5α-reductase (CYP19A1) in EC. Moreover, we aimed to investigate SRD5A2 and CYP19A1 expression in type 1 endometrial cancer and normal endometrium with its correlation to selected clinicopathological features...
November 28, 2017: Gynecological Endocrinology
https://www.readbyqxmd.com/read/29178922/elevated-plasma-levels-of-lysophosphatidic-acid-and-aberrant-expression-of-lysophosphatidic-acid-receptors-in-adenomyosis
#18
Bicheng Yang, Liqun Wang, Xiaoju Wan, Yunjun Li, Xiaohong Yu, Yunna Qin, Yong Luo, Feng Wang, Ouping Huang
BACKGROUND: Given the important roles of the receptor-mediated lysophosphatidic acid (LPA) signaling in both reproductive tract function and gynecological cancers, it will be informative to investigate the potential role of LPA in the development of adenomyosis. The objective of this study was to evaluate the levels of LPA in plasma and the expression of six LPA receptors in the endometrial tissue collected from women with and without adenomyosis. METHODS: Plasma and endometrial tissue samples were collected form women with and without adenomyosis...
November 25, 2017: BMC Women's Health
https://www.readbyqxmd.com/read/29162771/in-vivo-evidence-for-possible-up-regulating-roles-of-lysophosphatidic-acid-around-fertilization-in-rats
#19
Tae Takeda, Miki Shirasaka, Makoto Sugiyama, Ryota Terashihma, Mitsumori Kawaminami, Shiro Kurusu
Lysophosphatidic acid (LPA) produced by autotaxin (ATX) is recognized as a multi-functional mediator in mammalian reproduction. This study focused on possible effect(s) of LPA on ovulated cumulus-oocyte complexes (COCs) around fertilization in rats in vivo. Immunohistochemistry revealed the cell-type-dependent localization of candidates of synthetic enzymes, ATX and two phospholipases A2 isofroms, and LPA receptors LPA1~4 in ovulated COCs and in oviductal epithelium. The eggs ovulated with a form of COCs became denuded of cumulus cells and underwent fragmentation in the absence of fertilization...
November 21, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/29128569/lysophosphatidic-acid-receptor-1-is-important-for-intestinal-epithelial-barrier-function-and-susceptibility-to-colitis
#20
Songbai Lin, Yiran Han, Kayte Jenkin, Sei-Jung Lee, Maiko Sasaki, Jan-Michael Klapproth, Peijian He, C Chris Yun
Intestinal epithelial cells form a barrier that is critical in protecting the host from the hostile luminal environment. Previously, we showed that lysophosphatidic acid receptor 1 (LPAR1) regulates proliferation of intestinal epithelial cells such that the absence of LPA1 mitigates epithelial wound healing process. This study provides evidence that LPA1 is important for the maintenance of epithelial barrier integrity. The epithelial permeability, determined by fluorescently labeled dextran flux and transepithelial resistance, is increased in Lpar1(-/-) (Lpa1(-/-)) mouse intestine...
November 8, 2017: American Journal of Pathology
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