A novel indole compound, AWT-489, inhibits prostaglandin D2-induced CD55 expression by acting on DP prostanoid receptors as an antagonist in LS174T human colon cancer cells

Oyama, Satomi; Fujino, Hiromichi; Yamazaki, Risa; Okura, Iori; Regan, John W.; Awata, Atsuko; Arai, Takayoshi; Murayama, Toshihiko

doi:10.1016/j.abb.2013.10.023

Cited by 5 publications

(9 citation statements)

References 27 publications

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“…F, G). In addition, the control untransfected parental HEK cells showed some PGD 2 ‐ or PGE 2 ‐induced cAMP formation and TCF/β‐catenin signals, which were approximately 100 times lower than the receptor‐transfected cells (data not shown), as we have shown previously . Therefore, the contributions of the expression levels of endogenous prostanoid receptors to the transfected receptors were considerably weaker and have negligible effects.…”

Section: Resultssupporting

confidence: 61%

Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

et al. 2016

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Human D-type prostanoid (DP) and E-type prostanoid 2 (EP2) receptors are G protein-coupled receptors and are regarded as the most closely related receptors among prostanoid receptors because they are generated by tandem duplication. The DP receptor-cognate ligand, prostaglandin D (PGD ) has the ability to activate not only DP receptors but also EP2 receptors. Likewise, the EP2 receptor-cognate ligand, prostaglandin E (PGE ) has the ability to activate DP receptors in addition to EP receptors in order to stimulate cAMP formation. However, since PGD and/or PGE activate DP and EP2 receptors to similar maximal levels, that is, their similar efficacies, differences between the ligands in each receptor have not yet been determined in detail except for their different affinities. Herein we demonstrated, using an in silico simulation to predict binding patterns among DP or EP2 receptors and PGD , PGE , or prostaglandin F as the reference prostanoid, that DP and EP2 receptors plausibly take on distinct forms depending on the diverse binding of different ligands. Since these ligands have the potential to make these receptors form distinct conformations with discrete signaling pathways, they are consequently regarded as endogenous biased ligands. Moreover, by using functional assays, the susceptibilities of the DP receptors to the noncognate ligands were approximately 10 times lower than those of EP2 receptors. Thus, EP2 receptors seem to be able to distinguish endogenous ligands better than DP receptors, thereby both receptors are plausibly gaining role-sharing functions with respect to one another as the copies of duplicated gene.

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Section: Resultssupporting

confidence: 61%

Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

et al. 2016

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“…After the termination of experiments by removing the medium and placing plates on ice, the cAMP that formed was measured as described previously, 16) which was estimated from a standard curve obtained using non-radiolabeled cAMP.…”

Section: Methodsmentioning

confidence: 99%

“…19) Cell Culture, Cell Counts, and Materials LS174T human colon cancer cells were maintained in Minimum Essential Medium-α (α-MEM; Invitrogen, Carlsbad, CA, U.S.A.) containing 5% fetal bovine serum (FBS; Thermo Scientific, Waltham, MA, U.S.A.), 100 IU/mL penicillin (Meiji Seika, Japan), and 100 µg/mL streptomycin (Meiji Seika) at 37°C. HEK-293 Epstein-Barr virus, nuclear antigen (EBNA) cells stably expressing the human EP2 receptor or DP receptor, HEK-EP2 cells or HEK-DP cells, respectively, were as described previously, 16,20) which were cultured at 37°C in Dulbecco's modified Eagle's medium (DMEM; Nacalai Tesque, Japan) containing 10% FBS, 250 µg/mL hygromycin B (Enzo Life Sciences, Farmingdale, NY, U.S.A.), and 100 µg/mL gentamicin (Life Technologies, Carlsbad, CA, U.S.A.) as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…1C, MW-03 did not significantly reduce the expression of EP2 receptors, except for the 10 µM treatment. LS174T cells also express DP receptors 16) ; therefore, the effects of MW-03 were examined. DP receptor expression was not significantly altered by the treatment with MW-03, as shown in Fig.…”

Section: Effects Of Mw-03 On Pge 2 -Induced Camp Formationmentioning

confidence: 99%

“…[8][9][10] Thus, another possibility is that the inhibitory effects of MW-03 on PGE 2 -stimulated cAMP formation are due to the antagonistic effects of MW-03 on EP2 and/or DP receptors, which are expressed in LS174T cells. 8,16) In order to test this possibility, HEK-293 cells stably expressing either human EP2 receptors or DP receptors were pretreated with MW-03 for 15 min and then treated with 1 nM PGE 2 in HEK-EP2 cells and/or with 1 nM PGD 2 in HEK-DP cells, and cAMP formation was examined. The novel indole compound MW-03 (A).…”

Section: Effects Of Mw-03 On Pge 2 -Induced Camp Formationmentioning

confidence: 99%

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Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line

Seira

Yanagisawa

Suganami

et al. 2017

Biological & Pharmaceutical Bulletin

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Increases in the expression of prostaglandin E 2 (PGE 2 ) are widely known to be involved in aberrant growth in the early stage of colon cancer development. We herein demonstrated that the novel indole compound MW-03 reduced PGE 2 -induced cAMP formation by catalization to an inactive metabolite by inducing 15-hydroxyprostaglandin dehydrogenase through the activation of peroxisome proliferator-activated receptor-γ. MW-03 also inhibited colon cancer cell growth by arresting the cell cycle at the S phase. Although the target of MW-03 for cell cycle inhibition has not yet been identified, these dual anti-cancer effects of MW-03 itself and/or its leading compound(s) on colon cancer cells may reduce colon cancer development and, thus, have potential as a novel treatment for the early stage of this disease.Key words indole compound; MW-03; prostaglandin E 2 ; 15-hydroxyprostaglandin dehydrogenase; peroxisome proliferator-activated receptor-γ; colon cancer One major prostanoid, prostaglandin E 2 (PGE 2 ) is widely known to be up-regulated by the action of increased levels of cyclooxygenase-2 (COX-2) in colorectal cancer.1,2) Thus, the enhanced expression of COX-2 and biosynthesis of PGE 2 are responsible for the malignancy of diseases.1,2) Since the overexpression of COX-2 and PGE 2 is frequently observed in the early stage of colorectal cancer development, they are considered to be the biomarkers of this stage. 3)Cruciferous vegetables, such as cauliflower, cabbage, and broccoli, are regarded as good food sources for reducing the risk of cancer including colon cancer. 4,5) Natural compounds that contain indole structures are relatively rich in cruciferous vegetables. 4,5) The consumption of cruciferous vegetables has been recommended by the National Research Council in the United States because of the protective mechanisms of phytochemicals including derivatives of indoles, e.g. indole-3-carbinol and diindolylmethane.4,5) These indole derivatives have been shown to induce cancer cell death such as apoptosis; although many mechanisms are suggested and reported, 4,5) the exact mechanisms underlying currently remain unclear. These cell death mechanisms are not only exerted by phytochemical indoles, but also by synthesized indoles such as one popular non-steroidal anti-inflammatory drug (NSAID), indomethacin. 6,7)Some indole compounds have been used as tools for researching prostanoid receptors and/or their signaling pathways. Among them, indomethacin has been used as an E-type prostanoid 2 (EP2) prostanoid receptor antagonist, 8) D-type prostanoid receptor antagonist, 9,10) chemoattractant receptorhomologous molecule expressed on T helper 2 cell receptor agonist, 11) and peroxisome proliferator-activated receptor-γ (PPARγ) agonist/antagonist, 12,13) by itself and/or its leading compounds with cyclooxygenase inhibition-independent activities.14) A previous study reported that indomethacin induced 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catalyzes prostanoids such as PGE 2 to inactive, the metabolite...

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Why PGD₂ has different functions from PGE₂

Fujino

2020

BioEssays

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Prostaglandin (PG) D2 and PGE2 are positional isomers; however, they sometimes exhibit opposite physiological functions, such as in cancer development. Because DP receptors are considered to be a duplicated copy of EP2 receptors, PGD2 and PGE2 cross‐react with both receptors. These prostanoids may act as biased agonists for each receptor. In reviewing this field, a hypothesis was proposed to explain the opposed effects of these prostanoids from the viewpoints of the evolution of, mutations in, and biased activities of their receptors. Previous findings showing more mutations/variations in DP receptors than EP2 receptors among individuals worldwide indicate that DP receptors are still in a rapid evolutionary stage. The opposing effects of these prostanoids on cancer development may be attributed to the biased activity of PGE2 for DP receptors, which may incidentally develop during the process of the old ligand, PGE2 gaining selectivity to newly diverged DP receptors.

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A novel indole compound, AWT-489, inhibits prostaglandin D2-induced CD55 expression by acting on DP prostanoid receptors as an antagonist in LS174T human colon cancer cells

Cited by 5 publications

References 27 publications

Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line

Why PGD₂ has different functions from PGE₂

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A novel indole compound, AWT-489, inhibits prostaglandin D2-induced CD55 expression by acting on DP prostanoid receptors as an antagonist in LS174T human colon cancer cells

Cited by 5 publications

References 27 publications

Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line

Why PGD2 has different functions from PGE2

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Why PGD₂ has different functions from PGE₂