Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid

Uchiyama, Ayako; Mukai, Mutsuko; Fujiwara, Yuko; Kobayashi, Susumu; Kawai, Nobuyuki; Murofushi, Hiromu; Inoue, Masahiro; Enoki, Shigenori; Tanaka, Yuichiro; Niki, Tamotsu; Kobayashi, Tetsuyuki; Tigyi, Gábor; Murakami‐Murofushi, Kimiko

doi:10.1016/j.bbalip.2006.10.001

Cited by 59 publications

(74 citation statements)

References 26 publications

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“…NAG was purchased from Cayman Chemical (Ann Arbor, MI). CCPA 16:1 and 18:1 were provided by Dr. Susumu Kobayashi (University of Tokyo, Tokyo, Japan) (31). Accurate concentrations of phospholipids were measured by phosphate assays (32), and lipids were prepared before use as 1 mM stocks in PBS containing 1 mM charcoal-stripped bovine serum albumin (BSA).…”

Section: Methodsmentioning

confidence: 99%

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

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138

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Lysophosphatidic acid (LPA) is a ligand for LPA 1-3 of the endothelial differentiation gene family G-protein-coupled receptors, and LPA 4 -8 is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA 5 is limited and whether LPA is its preferred endogenous ligand has been questioned in the literature, in this study we applied a combination of computational and experimental site-directed mutagenesis of LPA 5 residues predicted to interact with the headgroup of LPA. Four residues involved in ligand recognition in LPA 5 were identified as follows: R2.60N mutant abolished receptor activation, whereas H4.64E, R6.62A, and R7.32A greatly reduced receptor activation. We also investigated the SAR of LPA 5 using LPA analogs and other non-lysophospholipid ligands. SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates Ͼ Ͼ N-arachidonoylglycine. These results confirm LPA 5 to be a bona fide lysophospholipid receptor. We also evaluated several compounds with previously established selectivity for the endothelial differentiation gene receptors and found several that are LPA 5 agonists. A pharmacophore model of LPA 5 binding requirements was developed for in silico screening, which identified two non-lipid LPA 5 antagonists. Because LPA 5 transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA 5 antagonists inhibit platelet activation. The present results suggest that selective inhibition of LPA 5 may provide a basis for future anti-thrombotic therapies.Lysophosphatidic acid (LPA, 2 1-radyl-2-hydroxy-sn-3-glycero phosphate) specifically interacts with several protein targets that regulate physiological and pathophysiological processes (1-3). LPA targets include specific G-protein-coupled receptors (GPCRs) that mediate a wide variety of biological effects, including cell proliferation (4), cell survival (5), cell migration (6), and platelet aggregation (7,8). GPCRs are the largest family of transmembrane receptors and represent targets of many therapeutics (9). Eight LPA-specific mammalian GPCRs, LPA 1-8 , have been identified to date (10 -12). Among the eight LPA receptors, LPA 1 , LPA 2 , and LPA 3 are members of the endothelial differentiation gene (EDG) family (13), and the transmembrane domains of human LPA 1-3 show 81% homology with each other (14). The five other members of the EDG family are specific for the related lysophospholipid sphingosine 1-phosphate (S1P). The structural foundation for LPA selectivity over S1P has been linked to a single amino acid at position 3.29, a conserved glutamine in the LPA-specific and glutamate in the S1P-specific members of the EDG family (14 -16). However, the recently identified non-EDG family LPA receptors, LPA 4 /p2y9 (13), LPA 5 /GPR92 (17, 18), LPA 6 /GPR87 (19), LPA 7 /p2y5 (12), and LPA 8 /p2y10 (10), are more closely related to the purinoreceptor gene cluster and share less than 20% amino acid...

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Section: Methodsmentioning

confidence: 99%

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

Self Cite

138

140

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“…Carba cyclic phosphatidic acids, 3ccPA and 2ccPA, were chemically synthesized according to Uchiyama et al [29]. Purity of cPA or ccPA were confirmed by TLC and negative ion liquid chromatography-mass spectrometry (data not shown).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

Cyclic phosphatidic acid influences the expression and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells

Tsukahara

Hanazawa

Murakami‐Murofushi

2011

Biochemical and Biophysical Research Communications

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Cyclic phosphatidic acid (cPA) is found in cells from slime mold to humans and has a largely unknown function. We previously reported that cPA significantly inhibited the lipid accumulation in 3T3-L1 adipocytes through inhibition of PPARγ activation. We find here that cPA reduced intracellular triglyceride levels and inhibited the phosphodiesterase 3B (PDE3B) expression in 3T3-L1 adipocytes. PPARγ activation in adipogenesis that can be blocked by treatment with cPA then participates in adipocyte function through inhibition of PDE3B expression. We also found the intracellular cAMP levels in 3T3-L1 adipocytes increased after exposure to cPA. These findings contribute to the participation of cPA on the lipolytic activity in 3T3-L1 adipocytes. Our studies imply that cPA might be a therapeutic compound in the treatment of obesity and obesity-related diseases.3

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“…GTP-bound, active forms of RhoA (Uchiyama et al 2007), Rac1, Cdc42 (Sander et al 1998) were determined by pull-down assay techniques as described previously. Briefly, cell lysates were incubated with GST-Rhotekin RBD (for active Rho) or GST-PAK CRIB domain (for active Rac and Cdc42) immobilized onto Glutathione-Sepharose 4B beads (GE Healthcare, UK) at 4°C for 45 min.…”

Section: Determination Of the Activities Of Rhoa Rac1 And Cdc42mentioning

confidence: 99%

Cdc42/N-WASP and Rac1/WAVE2 Required for LPA-induced Migration of Rat Ascites Hepatoma Cells

2010

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Summary Lysophosphatidic acid (LPA) has been shown to stimulate transcellular migration of MM1 rat ascites hepatoma cells through transient activation of the Rho/ROCK pathway. Here we report that LPA also induces transient inactivation of Cdc42 and Rac1, both of which are required for transmigration of MM1 cells. Cdc42-induced shape change is a required step for LPA-induced MM1 cell migration. We provide evidence that MM1 cells transmigrate the mesothelial cell monolayer through activation of not only previously reported Rho/ROCK pathway but also Rac/WAVE2 and Cdc42/N-WASP pathways.

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Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid

Cited by 59 publications

References 26 publications

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Cyclic phosphatidic acid influences the expression and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells

Cdc42/N-WASP and Rac1/WAVE2 Required for LPA-induced Migration of Rat Ascites Hepatoma Cells

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