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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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2
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Babalola KT, Arora M, Ganugula R, Agarwal SK, Mohan C, Kumar MNVR. Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes. Pharmacol Rev 2024; 76:228-250. [PMID: 38351070 PMCID: PMC10877736 DOI: 10.1124/pharmrev.123.000938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 11/21/2023] [Accepted: 12/06/2023] [Indexed: 02/16/2024] Open
Abstract
The role of advanced drug delivery strategies in drug repositioning and minimizing drug attrition rates, when applied early in drug discovery, is poised to increase the translational impact of various therapeutic strategies in disease prevention and treatment. In this context, drug delivery to the lymphatic system is gaining prominence not only to improve the systemic bioavailability of various pharmaceutical drugs but also to target certain specific diseases associated with the lymphatic system. Although the role of the lymphatic system in lupus is known, very little is done to target drugs to yield improved clinical benefits. In this review, we discuss recent advances in drug delivery strategies to treat lupus, the various routes of drug administration leading to improved lymph node bioavailability, and the available technologies applied in other areas that can be adapted to lupus treatment. Moreover, this review also presents some recent findings that demonstrate the promise of lymphatic targeting in a preclinical setting, offering renewed hope for certain pharmaceutical drugs that are limited by efficacy in their conventional dosage forms. These findings underscore the potential and feasibility of such lymphatic drug-targeting approaches to enhance therapeutic efficacy in lupus and minimize off-target effects of the pharmaceutical drugs. SIGNIFICANCE STATEMENT: The World Health Organization estimates that there are currently 5 million humans living with some form of lupus. With limited success in lupus drug discovery, turning to effective delivery strategies with existing drug molecules, as well as those in the early stage of discovery, could lead to better clinical outcomes. After all, effective delivery strategies have been proven to improve treatment outcomes.
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Affiliation(s)
- K T Babalola
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - M Arora
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - R Ganugula
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - S K Agarwal
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - C Mohan
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
| | - M N V Ravi Kumar
- The Center for Convergent Bioscience and Medicine (CCBM) (K.T.B., M.A., R.G., M.N.V.R.K.), Division of Translational Science and Medicine, College of Community Health Sciences (K.T.B., M.A., R.G., M.N.V.R.K.), Alabama Life Research Institute (K.T.B., M.A., R.G., M.N.V.R.K.), and Department of Biological Sciences (M.A., R.G., M.N.V.R.K.), The University of Alabama, Tuscaloosa, Alabama; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, Texas (S.K.A.); Department of Biomedical Engineering, University of Houston, Houston, Texas (C.M.); Chemical and Biological Engineering, University of Alabama, Tuscaloosa, Alabama (M.N.V.R.K.); and Center for Free Radical Biology (M.N.V.R.K.) and Nephrology Research and Training Center, Division of Nephrology, Department of Medicine (M.N.V.R.K.), University of Alabama at Birmingham, Birmingham, Alabama
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3
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Mushtaq U. EP1 receptor: Devil in emperors coat. J Cell Biochem 2023; 124:1105-1114. [PMID: 37450673 DOI: 10.1002/jcb.30436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/20/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023]
Abstract
EP1 receptor belongs to prostanoid receptors and is activated by prostaglandin E2. The receptor performs contrasting functions in central nervous system (CNS) and other tissues. Although the receptor is neurotoxic and proapoptotic in CNS, it has also been reported to act in an antiapoptotic manner by modulating cell survival, proliferation, invasion, and migration in different types of cancers. The receptor mediates its neurotoxic effects by increasing cytosolic Ca2+ levels, leading to the activation of its downstream target, protein kinase C, in different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and epilepsy. Antagonists ONO-8713, SC51089, and SC51322 against EP1 receptor ameliorate the neurotoxic effect by attenuating the neuroinflammation. The receptor also shows increased expression in different types of cancers and has been found to activate different signaling pathways, which lead to the development, progression, and metastasis of different cancers. The receptor stimulates the cell survival pathway by phosphorylating the AKT and PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways. Although there are limited studies about this receptor and not a single clinical trial has been targeting the EP1 receptor for different neurological disorders or cancer, the receptor is appearing as a potential candidate for therapeutic targets. The aim of this article is to review the recent progress in understanding the pathogenic roles of EP1 receptors in different pathological conditions.
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Affiliation(s)
- Umar Mushtaq
- Department of Biotechnology, Central University of Kashmir, Ganderbal, India
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4
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Rovati G, Contursi A, Bruno A, Tacconelli S, Ballerini P, Patrignani P. Antiplatelet Agents Affecting GPCR Signaling Implicated in Tumor Metastasis. Cells 2022; 11:725. [PMID: 35203374 PMCID: PMC8870128 DOI: 10.3390/cells11040725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 11/16/2022] Open
Abstract
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial-mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A2, and prostaglandin (PG) E2, act through G protein-coupled receptors (GPCRs) to cause the activation of more additional platelets and drive metastatic signaling pathways in cancer cells. In this review, we examine the contribution of the GPCRs of platelets and cancer cells in the development of cancer metastasis. Finally, the possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed.
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Affiliation(s)
- Gianenrico Rovati
- Department of Pharmaceutical Sciences, University of Milan, 20122 Milan, Italy;
| | - Annalisa Contursi
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Annalisa Bruno
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Stefania Tacconelli
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Patrizia Ballerini
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Innovative Technologies in Medicine and Dentistry, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Paola Patrignani
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
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5
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Wang Q, Morris RJ, Bode AM, Zhang T. Prostaglandin Pathways: Opportunities for Cancer Prevention and Therapy. Cancer Res 2021; 82:949-965. [PMID: 34949672 DOI: 10.1158/0008-5472.can-21-2297] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/27/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022]
Abstract
Because of profound effects observed in carcinogenesis, prostaglandins (PGs), prostaglandin-endoperoxide synthases, and PG receptors are implicated in cancer development and progression. Understanding the molecular mechanisms of PG actions has potential clinical relevance for cancer prevention and therapy. This review focuses on the current status of PG signaling pathways in modulating cancer progression and aims to provide insights into the mechanistic actions of PGs and their receptors in influencing tumor progression. We also examine several small molecules identified as having anticancer activity that target prostaglandin receptors. The literature suggests that targeting PG pathways could provide opportunities for cancer prevention and therapy.
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Affiliation(s)
- Qiushi Wang
- The Hormel Institute, University of Minnesota
| | | | - Ann M Bode
- The Hormel Institute, University of Minnesota
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6
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Masato M, Miyata Y, Kurata H, Ito H, Mitsunari K, Asai A, Nakamura Y, Araki K, Mukae Y, Matsuda T, Harada J, Matsuo T, Ohba K, Sakai H. Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model. Sci Rep 2021; 11:20279. [PMID: 34645904 PMCID: PMC8514456 DOI: 10.1038/s41598-021-99694-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/24/2021] [Indexed: 12/23/2022] Open
Abstract
Prostaglandin E2 plays an important role in carcinogenesis and malignant potential of prostate cancer (PC) cells by binding to its specific receptors, E-type prostanoid (EP) receptors. However, anti-carcinogenic effects of the EP receptor antagonist are unclear. In this study, we used a mouse model of PC. The mice were provided standard feed (control) or feed containing the EP1 receptor antagonist and were sacrificed at 10, 15, 30, and 52 weeks of age. Apoptosis was evaluated by immunohistochemical analysis using a cleaved caspase-3 assay. The incidence of cancer in the experimental group was significantly lower than that in the control group at 15, 30, and 52 weeks of age. The percentage of poorly differentiated PC cells was significantly lower in the experimental group than in the control group at 30 and 52 weeks of age. The percentage of apoptotic cells in the experimental group was significantly higher than that in the control group at 15, 30, and 52 weeks of age. These findings indicate that feeding with the addition of EP1 receptor antagonist delayed PC progression via the upregulation of apoptosis. We suggest that the EP1 receptor antagonist may be a novel chemopreventive agent for PC.
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Affiliation(s)
- Masahito Masato
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yasuyoshi Miyata
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Hiroki Kurata
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Hidenori Ito
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kensuke Mitsunari
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Akihiro Asai
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yuichiro Nakamura
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kyohei Araki
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yuta Mukae
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Tsuyoshi Matsuda
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Junki Harada
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Tomohiro Matsuo
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kojiro Ohba
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Hideki Sakai
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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Tabana Y, Okoye IS, Siraki A, Elahi S, Barakat KH. Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis. Front Oncol 2021; 11:628138. [PMID: 33747948 PMCID: PMC7973280 DOI: 10.3389/fonc.2021.628138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
The burden of breast cancer is imposing a huge global problem. Drug discovery research and novel approaches to treat breast cancer have been carried out extensively over the last decades. Although immune checkpoint inhibitors are showing promising preclinical and clinical results in treating breast cancer, they are facing multiple limitations. From an immunological perspective, a recent report highlighted breast cancer as an "inflamed tumor" with an immunosuppressive microenvironment. Consequently, researchers have been focusing on identifying novel immunological targets that can tune up the tumor immune microenvironment. In this context, several novel non-classical immune targets have been targeted to determine their ability to uncouple immunoregulatory pathways at play in the tumor microenvironment. This article will highlight strategies designed to increase the immunogenicity of the breast tumor microenvironment. It also addresses the latest studies on targets which can enhance immune responses to breast cancer and discusses examples of preclinical and clinical trial landscapes that utilize these targets.
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Affiliation(s)
- Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Isobel S. Okoye
- School of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Arno Siraki
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- School of Dentistry, University of Alberta, Edmonton, AB, Canada
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Khaled H. Barakat
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
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Salim E, El-Sisi AED, Sokar S, El-Sayad M, Moussa E. Metformin potentiates the chemotherapeutic effects of doxorubicin on 2-amino-1-methyl-6-phenylimidazo[4,5b] pyridine-induced Mammary Carcinoma in rats. Fundam Clin Pharmacol 2020; 35:700-713. [PMID: 32905620 DOI: 10.1111/fcp.12604] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/20/2020] [Accepted: 09/02/2020] [Indexed: 11/28/2022]
Abstract
This study was carried out to evaluate the antitumor activity of Metformin (Met) and its impending utility to potentiate the chemotherapeutic action of doxorubicin on 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP)-induced rat mammary carcinogenesis. Female Sprague -Dawley (SD) rats were divided into seven groups (n = 15 each). Mammary carcinogenesis was induced by the administration of PhIP at a dose of 75 mg/kg by gavage. Met treatment was 2 mg/ml in drinking water for 26 weeks started after the last PhIP dose. Doxorubicin (Dox) treatment started after one month of the last PhIP dose with a dose of 4 mg/kg, i.v. once per week for 4 weeks. Compared to the PhIP group, the latency period of tumors in the PhIP+Dox, PhIP+Met, and PhIP+Dox+Met groups were significantly increased and tumors' incidences and multiplicities were significantly reduced. By immunohistochemistry, carcinomas from the combination treatment groups showed a significant decrease in the labeling indexes (LI%) of cellular proliferation and CD44 compared to the PhIP group while LI% for ERα was significantly decreased in all combination treatment groups compared to the PhIP-administered group. Moreover, the quantitative mRNA expression of ERα was significantly decreased in mammary tumors from PhIP + Dox+Met combined group more than the PhIP + Dox group. However, mRNA expression of EGF was found significantly lower in all combination treatment groups compared to the PhIP group. These findings suggest that Metformin potentiate the antitumor efficacy of doxorubicin and had beneficial effects on PhIP-induced mammary carcinogenesis through the prevention of cellular proliferation and mRNA expression of ERα and EGF.
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Affiliation(s)
- Elsayed Salim
- Department of Zoology, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Alaa El-Din El-Sisi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Samia Sokar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Magda El-Sayad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Ethar Moussa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
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9
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Hester A, Salzmann B, Rahmeh M, Kolben T, Czogalla B, Ditsch N, Mahner S, Jeschke U, Kolben TM. EP3 receptor antagonist L798,106 reduces proliferation and migration of SK-BR-3 breast cancer cells. Onco Targets Ther 2019; 12:6053-6068. [PMID: 31534346 PMCID: PMC6680222 DOI: 10.2147/ott.s204919] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 04/11/2019] [Indexed: 01/02/2023] Open
Abstract
Purpose: COX-2 overexpression and elevated levels of prostaglandin E2 (PGE2) play an important role in breast cancer carcinogenesis. Recently, expression of the PGE2 receptor EP3 has been shown to be a positive prognostic factor in breast cancer. This study analyzes the functional aspects of targeting EP3 in breast cancer cell lines. Material and methods: EP3 and EP1 expressions were determined in five breast cancer cell lines on the mRNA- and the protein-level. The selected cell lines were subsequently stimulated for 24-72 hrs with 10-1,000 nM of PGE2, the EP1/EP3 agonist sulprostone and the EP3 antagonist L798,106. Cell proliferation was determined via BrdU-assay, migration via scratch assay, EP3, Gi-protein and p-ERK1/2 expressions via Western blot and cAMP concentrations via ELISA. The Mann-Whitney-U-test was used to test for statistical significance. Results: The cell lines T-47D (EP3 expression 77.7%) and SK-BR-3 (EP3 expression 48.7%) were chosen. EP3 antagonism reduced its expression on SK-BR-3 significantly, while no effect was observed on T-47D. The proliferation and migration of SK-BR-3 cells were significantly reduced due to treatment with the EP1/3 agonist, the EP3 antagonist or a combination of both. Neither agonism nor antagonism influenced cell proliferation or migration in T-47D. In SK-BR-3, EP3 antagonism showed a significant decrease in Gi-protein levels, an increase in cAMP levels, and no significant change in p-ERK1/2 expression. Conclusion: Antagonism of the EP3 receptor results in a reduced proliferation and migration of SK-BR-3 breast cancer cells, potentially mediated via a Gi-protein-cAMP pathway. The results suggest that EP3 plays a role in tumorigenesis. This is in accordance with the cell culture data of other gynecological tumors, but it is conflicting in so far, as positive EP3 expression is clinically a positive prognostic marker in breast cancer. Therefore, other factors may be important in explaining this contradiction.
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Affiliation(s)
- Anna Hester
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Barbara Salzmann
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Martina Rahmeh
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Thomas Kolben
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Bastian Czogalla
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Nina Ditsch
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Theresa Maria Kolben
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
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10
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Basudhar D, Bharadwaj G, Somasundaram V, Cheng RYS, Ridnour LA, Fujita M, Lockett SJ, Anderson SK, McVicar DW, Wink DA. Understanding the tumour micro-environment communication network from an NOS2/COX2 perspective. Br J Pharmacol 2019; 176:155-176. [PMID: 30152521 PMCID: PMC6295414 DOI: 10.1111/bph.14488] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/31/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022] Open
Abstract
Recent findings suggest that co-expression of NOS2 and COX2 is a strong prognostic indicator in triple-negative breast cancer patients. These two key inflammation-associated enzymes are responsible for the biosynthesis of NO and PGE2 , respectively, and can exert their effect in both an autocrine and paracrine manner. Impairment of their physiological regulation leads to critical changes in both intra-tumoural and intercellular communication with the immune system and their adaptation to the hypoxic tumour micro-environment. Recent studies have also established a key role of NOS2-COX2 in causing metabolic shift. This review provides an extensive overview of the role of NO and PGE2 in shaping communication between the tumour micro-environment composed of tumour and immune cells that in turn favours tumour progression and metastasis. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.
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Affiliation(s)
- Debashree Basudhar
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Gaurav Bharadwaj
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Veena Somasundaram
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Robert Y S Cheng
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Lisa A Ridnour
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Mayumi Fujita
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
- Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and TechnologyChiba‐kenJapan
| | - Stephen J Lockett
- Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. for the National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Stephen K Anderson
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - Daniel W McVicar
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
| | - David A Wink
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthFrederickMDUSA
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11
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GPCR Modulation in Breast Cancer. Int J Mol Sci 2018; 19:ijms19123840. [PMID: 30513833 PMCID: PMC6321247 DOI: 10.3390/ijms19123840] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 11/22/2018] [Accepted: 11/27/2018] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors involved in the development and progression of many tumors including breast cancer. Here we discuss data regarding GPCR-mediated signaling, pharmacological properties and biological outputs toward breast cancer tumorigenesis and metastasis. Furthermore, we address several drugs that have shown an unexpected opportunity to interfere with GPCR-based breast tumorigenic signals.
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12
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EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer. BMC Cancer 2018; 18:431. [PMID: 29661238 PMCID: PMC5902996 DOI: 10.1186/s12885-018-4286-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 03/21/2018] [Indexed: 11/30/2022] Open
Abstract
Background In various cancers, overexpression of cyclooxygenase (COX)-2 and elevated prostaglandin (PG) E2 synthesis have been associated with tumor development and progression. The potential of COX-2 inhibitors in cancer prevention and treatment has been shown repeatedly; however, their clinical use is limited due to toxicity. PGE2 signals via EP receptors 1–4, whose functions are analyzed in current research in search for targeted anti-PG therapies. EP2 and EP4 rather promote tumorigenesis, while the role of EP3, especially in breast cancer, is not yet clear and both pro- and anti-tumorigenic effects have been described. Our study evaluates EP3 receptor expression in sporadic breast cancer and its association with clinicopathological parameters, progression-free and overall survival. Methods Two hundred eighty-nine sporadic breast cancer samples without primary distant metastasis were immunohistochemically analyzed for EP3 receptor expression. Tissue was stained with primary anti-EP3-antibodies. Immunoreactivity was quantified by the immunoreactivity-score (IRS); samples with an IRS ≥ 2 scored as EP3 positive. Chi-squared and Mann-Whitney-U test were used for comparison of data; Kaplan-Meier estimates and Cox-regression were used for survival analyses. Results EP3 receptor was expressed in 205 of 289 samples analyzed (70.9%). EP3 receptor expression was not associated with clinicopathological parameters (e. g. tumor size, hormone receptors, lymph node status). Kaplan-Meier estimates showed a significant association of EP3 positivity with improved progression-free survival (p = 0.002) and improved overall survival (p = 0.001) after up to 10 years. Cox regression analysis confirmed EP3 positivity as a significant prognostic factor even when other known prognosticators were accounted for. Conclusions In sporadic breast cancer, EP3 receptor expression is not significantly associated with clinicopathological parameters but is a significant prognostic factor for improved progression-free and overall survival. However, the functional aspects of EP3 receptor in breast cancer and the way how EP3 may oppose the pro-tumorigenic effects of PGE2 elevation and COX-2 overexpression are not fully understood so far. Further studies aiming at identification of the factors regulated by EP3 are necessary to evaluate the possibility of targeting EP3 in future anti-tumor therapy in breast cancer. Electronic supplementary material The online version of this article (10.1186/s12885-018-4286-9) contains supplementary material, which is available to authorized users.
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13
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Alexanian A, Sorokin A. Cyclooxygenase 2: protein-protein interactions and posttranslational modifications. Physiol Genomics 2017; 49:667-681. [PMID: 28939645 DOI: 10.1152/physiolgenomics.00086.2017] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Numerous studies implicate the cyclooxygenase 2 (COX2) enzyme and COX2-derived prostanoids in various human diseases, and thus, much effort has been made to uncover the regulatory mechanisms of this enzyme. COX2 has been shown to be regulated at both the transcriptional and posttranscriptional levels, leading to the development of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX2 inhibitors (COXIBs), which inhibit the COX2 enzyme through direct targeting. Recently, evidence of posttranslational regulation of COX2 enzymatic activity by s-nitrosylation, glycosylation, and phosphorylation has also been presented. Additionally, posttranslational regulators that actively downregulate COX2 expression by facilitating increased proteasome degradation of this enzyme have also been reported. Moreover, recent data identified proteins, located in close proximity to COX2 enzyme, that serve as posttranslational modulators of COX2 function, upregulating its enzymatic activity. While the precise mechanisms of the protein-protein interaction between COX2 and these regulatory proteins still need to be addressed, it is likely these interactions could regulate COX2 activity either as a result of conformational changes of the enzyme or by impacting subcellular localization of COX2 and thus affecting its interactions with regulatory proteins, which further modulate its activity. It is possible that posttranslational regulation of COX2 enzyme by such proteins could contribute to manifestation of different diseases. The uncovering of posttranslational regulation of COX2 enzyme will promote the development of more efficient therapeutic strategies of indirectly targeting the COX2 enzyme, as well as provide the basis for the generation of novel diagnostic tools as biomarkers of disease.
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Affiliation(s)
- Anna Alexanian
- Cardiovascular Center and Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Andrey Sorokin
- Cardiovascular Center and Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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14
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Wang Y, Lai S, Tang J, Feng C, Liu F, Su C, Zou W, Chen H, Xu D. Prostaglandin E2 promotes human CD34+ cells homing through EP2 and EP4 in vitro. Mol Med Rep 2017; 16:639-646. [PMID: 28560401 PMCID: PMC5482140 DOI: 10.3892/mmr.2017.6649] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 03/31/2017] [Indexed: 12/29/2022] Open
Abstract
Recently, certain studies have demonstrated in vitro that prostaglandin E2 (PGE2) promotes human cluster of differentiation (CD)34+ cell homing. However, the sub-type receptors activated by PGE2 are unknown, as the PGE2 receptor EP1-4 subtypes (EP1-4) are expressed on the membrane of human CD34+ cells. Based on the above, the present study aimed to screen the receptor subtype activity by PGE2 to promote human CD34+ cell homing. It was observed that human CD34+ cells expressed the four PGE2 sub-receptors, particularly EP2 and 4. PGE2 increased EP2 and 4 mRNA expression significantly, while EP1 and 3 mRNA exhibited no significant alteration. PGE2, EP2 agonist (EP2A), and EP4A upregulated C-X-C chemokine receptor 4 mRNA and protein expression in human CD34+ cells, and promoted stromal cell-derived factor 1α (SDF-1α) expression in bone marrow mesenchymal stem cells (BMMSCs). These phenomena were inhibited by the associated receptor antagonists. PGE2, EP2A, and EP4A facilitated human CD34+ cell migration towards SDF-1α and BMMSCs. The results of the present study suggested that PGE2 promoted human CD34+ cell homing through EP2 and 4 receptors in vitro.
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Affiliation(s)
- Yaqun Wang
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Shuping Lai
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jing Tang
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chun Feng
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Fangjie Liu
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chang Su
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Waiyi Zou
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Huizhen Chen
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Duorong Xu
- Department of Hematology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
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15
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Yang HJ, Jiang JH, Yang YT, Yang XD, Guo Z, Qi YP, Zeng FH, Zhang KL, Chen NZ, Xiang BD, Li LQ. Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma, while prostaglandin receptor-1 expression predicts survival. World J Gastroenterol 2016; 22:8798-8805. [PMID: 27818595 PMCID: PMC5075554 DOI: 10.3748/wjg.v22.i39.8798] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/15/2016] [Accepted: 08/30/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP1) contribute to disease and whether they help predict prognosis.
METHODS We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.
RESULTS Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001).
CONCLUSION COX-2 expression appears to be linked to early HCC events (initiation), while EP1 receptor expression may participate in tumor progression and predict survival.
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16
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O'Callaghan G, Houston A. Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? Br J Pharmacol 2015; 172:5239-50. [PMID: 26377664 DOI: 10.1111/bph.13331] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 08/06/2015] [Accepted: 09/14/2015] [Indexed: 12/28/2022] Open
Abstract
Elevated expression of COX-2 and increased levels of PGE2 are found in numerous cancers and are associated with tumour development and progression. Although epidemiological, clinical and preclinical studies have shown that the inhibition of PGE2 synthesis through the use of either non-steroidal anti-inflammatory drugs (NSAIDs) or specific COX-2 inhibitors (COXibs) has the potential to prevent and treat malignant disease, toxicities due to inhibition of COX-2 have limited their use. Thus, there is an urgent need for the development of strategies whereby COX-2 activity may be reduced without inducing any side effects. The biological effects of PGE2 are mediated by signalling through four distinct E-type prostanoid (EP) receptors - EP1 , EP2 , EP3 and EP4 . In recent years, extensive effort has gone into elucidating the function of PGE2 and the EP receptors in health and disease, with the goal of creating selective inhibitors as a means of therapy. In this review, we focus on PGE2 , and in particular on the role of the individual EP receptors and their signalling pathways in neoplastic disease. As knowledge concerning the role of the EP receptors in cancer grows, so does the potential for exploiting the EP receptors as therapeutic targets for the treatment of cancer and metastatic disease.
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Affiliation(s)
- G O'Callaghan
- Department of Medicine, University College Cork, Cork, Ireland.,HRB Clinical Research Facility, University College Cork, Cork, Ireland
| | - A Houston
- Department of Medicine, University College Cork, Cork, Ireland.,Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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17
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Chang HH, Young SH, Sinnett-Smith J, Chou CEN, Moro A, Hertzer KM, Hines OJ, Rozengurt E, Eibl G. Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1. Am J Physiol Cell Physiol 2015; 309:C639-49. [PMID: 26310818 DOI: 10.1152/ajpcell.00417.2014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 08/14/2015] [Indexed: 02/07/2023]
Abstract
Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca(2+)-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca(2+) response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca(2+) signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.
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Affiliation(s)
- Hui-Hua Chang
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and
| | - Steven H Young
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - James Sinnett-Smith
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Caroline Ei Ne Chou
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and
| | - Aune Moro
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and
| | - Kathleen M Hertzer
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and
| | - Oscar Joe Hines
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and
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18
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Friedman EA, Ogletree ML, Haddad EV, Boutaud O. Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease. Thromb Res 2015; 136:493-503. [PMID: 26077962 DOI: 10.1016/j.thromres.2015.05.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 05/05/2015] [Accepted: 05/25/2015] [Indexed: 01/14/2023]
Abstract
The platelet thrombus is the major pathologic entity in acute coronary syndromes, and antiplatelet agents are a mainstay of therapy. However, individual patient responsiveness to current antiplatelet drugs is variable, and all drugs carry a risk of bleeding. An understanding of the complex role of Prostaglandin E2 (PGE2) in regulating thrombosis offers opportunities for the development of novel individualized antiplatelet treatment. However, deciphering the platelet regulatory function of PGE2 has long been confounded by non-standardized experimental conditions, extrapolation of murine data to humans, and phenotypic differences in PGE2 response. This review synthesizes past and current knowledge about PGE2 effects on platelet biology, presents a rationale for standardization of experimental protocols, and provides insight into a molecular mechanism by which PGE2-activated pathways could be targeted for new personalized antiplatelet therapy to inhibit pathologic thrombosis without affecting hemostasis.
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Affiliation(s)
- Eitan A Friedman
- Department of Medicine, Vanderbilt University, Nashville, TN 37232
| | - Martin L Ogletree
- PO Box 559, Bala Cynwyd, PA 19004; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232
| | - Elias V Haddad
- Department of Medicine, Vanderbilt University, Nashville, TN 37232
| | - Olivier Boutaud
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
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19
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Simper MS, Rundhaug JE, Mikulec C, Bowen R, Shen J, Lu Y, Lin K, Surh I, Fischer SM. The tumor promoting activity of the EP4 receptor for prostaglandin E2 in murine skin. Mol Oncol 2014; 8:1626-39. [PMID: 25034079 DOI: 10.1016/j.molonc.2014.06.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 06/21/2014] [Accepted: 06/23/2014] [Indexed: 10/25/2022] Open
Abstract
To determine whether the EP4 receptor for prostaglandin E2 (PGE2) contributes to the tumor promoting activity of PGs in murine skin, EP4 over-expressing mice (BK5.EP4) were generated and subjected carcinogenesis protocols. An initiation/promotion protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. An increase in SCCs also occurred following treatment with initiator alone or UV irradiation. The initiator dimethylbenz[a]anthracene caused cytotoxicity in BK5.EP4, but not WT mice, characterized by sloughing of the interfollicular epidermis, regeneration and subsequent SCC development. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, supporting a pro-tumorigenic role for the EP4 receptor.
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Affiliation(s)
- Melissa S Simper
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Joyce E Rundhaug
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Carol Mikulec
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Rebecca Bowen
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Jianjun Shen
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Yue Lu
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Kevin Lin
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Inok Surh
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Susan M Fischer
- The Department of Molecular Carcinogenesis, Science Park, PO Box 389, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
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20
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O'Callaghan G, Ryan A, Neary P, O'Mahony C, Shanahan F, Houston A. Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer. Int J Cancer 2013; 133:825-34. [PMID: 23390011 DOI: 10.1002/ijc.28076] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 01/16/2013] [Indexed: 12/14/2022]
Abstract
Despite studies demonstrating that inhibition of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2 ) has significant chemotherapeutic benefits in vitro and in vivo, inhibition of COX enzymes is associated with serious gastrointestinal and cardiovascular side effects, limiting the clinical utility of these drugs. PGE2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. Here, we show that targeted inhibition of the EP1 receptor in the tumor cells and the tumor microenvironment resulted in the significant inhibition of tumor growth in vivo. Both dietary administration and direct injection of the EP1 receptor-specific antagonist, ONO-8713, effectively reduced the growth of established CT26 tumors in BALB/c mice, with suppression of the EP1 receptor in the tumor cells alone less effective in reducing tumor growth. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4(+) CD25(+) Foxp3(+) regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased. F4/80(+) macrophage infiltration was also decreased; however, there was no change in macrophage phenotype. These findings suggest that the EP1 receptor represents a potential target for the treatment of colon cancer.
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21
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Miyata Y, Ohba K, Matsuo T, Watanabe SI, Hayashi T, Sakai H, Kanetake H. Tumor-associated stromal cells expressing E-prostanoid 2 or 3 receptors in prostate cancer: correlation with tumor aggressiveness and outcome by angiogenesis and lymphangiogenesis. Urology 2012; 81:136-42. [PMID: 23149328 DOI: 10.1016/j.urology.2012.08.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 07/24/2012] [Accepted: 08/08/2012] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To clarify the detailed pathologic roles of prostaglandin E(2) in prostate cancer tissues, the present study investigated the clinical significance and prognostic roles of the density of tumor-associated stromal cells expressing specific receptors for prostaglandin E2, termed "E-prostanoid (EP)1-4 receptors (EP1R-4Rs)." METHODS The expression of each receptor was immunohistochemically examined in 114 formalin-fixed biopsy specimens. Correlations with clinicopathologic features were investigated in these specimens. Angiogenesis and lymphangiogenesis were measured by the percentage of CD34-stained vessels (microvessel density) and D2-40-stained vessels (lymph vessel density). The relationships between the density of each EPR-stained cells and the microvessel density or lymph vessel density were evaluated in 62 prostate cancer tissues obtained by radical surgery for more detailed analysis in a wider area of prostate cancer tissue. RESULTS The density of tumor-associated cells with EP2R expression was positively associated with the N (P<.001) and M (P=.002) stages. Similarly, EP3R-positive stromal cell density was significantly associated with the N (P=.033) and M (P=.026) stages. The density of EP2R- and EP3R-stained cells correlated with the microvessel density (r=0.42, P<.001) and lymph vessel density (r=0.36, P=.012), respectively. A greater density of EP2R-stained cells was recognized as an independent predictor of progression (hazard ratio 7.26, P=.002) on multivariate analysis. CONCLUSION EP2R- and EP3R-stained cells might play important roles in tumor progression, angiogenesis, and lymphangiogenesis in prostate cancer. The density of EP2R-stained stromal cells could offer a useful predictor of biochemical recurrence after radical surgery.
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MESH Headings
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Biomarkers, Tumor/metabolism
- Disease Progression
- Humans
- Kaplan-Meier Estimate
- Lymphangiogenesis
- Male
- Multivariate Analysis
- Neoplasm Invasiveness
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Staging
- Neovascularization, Physiologic
- Proportional Hazards Models
- Prostate/cytology
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/pathology
- Receptors, Prostaglandin E, EP1 Subtype/metabolism
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP3 Subtype/metabolism
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Stromal Cells/metabolism
- Stromal Cells/pathology
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Affiliation(s)
- Yasuyoshi Miyata
- Department of Nephro-urology, Nagasaki University Graduate School of Biomedical Sciences, and Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan.
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22
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Xin X, Majumder M, Girish GV, Mohindra V, Maruyama T, Lala PK. Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model. J Transl Med 2012; 92:1115-28. [PMID: 22641101 DOI: 10.1038/labinvest.2012.90] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.
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Affiliation(s)
- Xiping Xin
- Departments of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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23
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Prostanoid EP1 receptor as the target of (-)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro. Acta Pharmacol Sin 2012; 33:701-9. [PMID: 22555372 DOI: 10.1038/aps.2012.13] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIM To investigate the effects of (-)-epigallocatechin-3-gallate (EGCG), an active compound in green tea, on prostaglandin E(2) (PGE(2))-induced proliferation and migration, and the expression of prostanoid EP(1) receptors in hepatocellular carcinoma (HCC) cells. METHODS HCC cell line HepG2, human hepatoma cell lines MHCC-97L, MHCC-97H and human hepatocyte cell line L02 were used. Cell viability was analyzed using MTT assay. PGE(2) production was determined with immunoassay. Wound healing assay and transwell filter assay were employed to assess the extent of HCC cell migration. The expression of EP(1) receptor and Gq protein were examined using Western blot assay. RESULTS PGE(2) (4-40000 nmol/L) or the EP(1) receptor agonist ONO-DI-004 (400-4000 nmol/L) increased the viability and migration of HepG2 cells in concentration-dependent manners. EGCG (100 μg/mL) significantly inhibited the viability and migration of HepG2 cells induced by PGE(2) or ONO-DI-004. HepG2 cells secreted an abundant amount of PGE(2) into the medium, and EGCG (100 μg/mL) significantly inhibited the PGE(2)production and EP(1) receptor expression in HepG2 cells. EGCG (100 μg/mL) also inhibited the viability of MHCC-97L cells, but not that of MHCC-97H cells. Both EGCG (100 μg/mL) and EP(1) receptor antagonist ONO-8711 inhibited PGE(2) 4 μmol/L and ONO-DI-004 400 nmol/L-induced growth and migration of HepG2 cells. Both EGCG (100 μg/mL) and ONO-8711 210 nmol/L inhibited PGE(2)- and ONO-DI-004-induced EP(1) expression. EGCG and ONO-8711 had synergistic effects in inhibiting EP(1) receptor expression. PGE(2), ONO-DI-004, ONO-8711, and EGCG had no effects on Gq expression in HepG2 cells, respectively. CONCLUSION These findings suggest that the anti-HCC effects of EGCG might be mediated, at least partially, through the suppressing EP(1) receptor expression and PGE(2) production.
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Abstract
One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE2. In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE2 and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE2 synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.
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25
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Abstract
Prostaglandins are lipid compounds that mediate many physiological effects. Prostaglandin E2 (PGE(2)) is the most abundant prostanoid in the human body, and synthesis of PGE(2) is driven by cyclooxygenase enzymes including COX-2. Both elevated expression of COX-2 and increased PGE(2) levels have been associated with many cancers including breast cancer. PGE(2) exerts its effect by binding to the E series of prostaglandin receptors (EP) which are G protein-coupled receptors. Four EP receptor subtypes exist, EP1-4, and each is coupled to different intracellular signaling pathways. As downstream effectors of the COX-2 pathway, EP receptors have been shown to play a role in breast and other malignancies and in cancer metastasis. The role of each EP receptor in malignant behavior is complex and involves the interplay of EP receptor signaling on the tumor cell, on stromal cells, and on host immune effector cells. While preclinical and epidemiological data support the use of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors (COXibs) for the prevention and treatment of malignancy, toxicities due to COXibs as well as less than promising results from clinical trials have laboratories seeking alternative targets. As knowledge concerning the role of EP receptors in cancer grows, so does the potential for exploiting EP receptors as therapeutic targets for the treatment or prevention of cancer and cancer metastasis.
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Affiliation(s)
- Jocelyn Reader
- University of Maryland Marlene and Stewart Greenebaum Cancer Center, 655 W Baltimore, St Baltimore, MD 21201, USA
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26
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Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2. Trends Mol Med 2012; 18:233-43. [PMID: 22425675 DOI: 10.1016/j.molmed.2012.02.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 02/10/2012] [Accepted: 02/14/2012] [Indexed: 02/06/2023]
Abstract
Prostanoids regulate angiogenesis in carcinoma and chronic inflammatory disease progression. Although prostanoid biosynthetic enzymes and signaling have been extensively analyzed in inflammation, little is known about how prostanoids mediate tumor-induced angiogenesis. Targeted cyclooxygenase (COX)-2 inhibition in tumor, stromal and endothelial cells is an attractive antiangiogenic strategy; however, the associated cardiovascular side effects have led to the development of a new generation of nonsteroidal anti-inflammatory drugs (NSAIDs) acting downstream of COX. These agents target terminal prostanoid synthases and prostanoid receptors, which may also include several peroxisome proliferator-activated receptors (PPARs). Here, we discuss the role of prostanoids as modulators of tumor angiogenesis and how prostanoid metabolism reflects complex cell-cell crosstalk that determines tumor growth. Finally, we discuss the potential of new NSAIDs for the treatment of angiogenesis-dependent tumor development.
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Abstract
Many lines of evidence demonstrate that prostaglandins play an important role in cancer, and enhanced synthesis of prostaglandin E(2) (PGE(2)) is often observed in various human malignancies often associated with poor prognosis. PGE(2) synthesis is initiated with the release of arachidonic acid by phospholipase enzymes, where it is then converted into the intermediate prostaglandin prostaglandin H(2) (PGH(2)) by members of the cyclooxygenase family. The synthesis of PGE(2) from PGH(2) is facilitated by three different PGE synthases, and functional PGE(2) can promote tumor growth by binding to four EP receptors to activate signaling pathways that control cell proliferation, migration, apoptosis, and angiogenesis. An integral method of controlling gene expression is by posttranscriptional mechanisms that regulate mRNA stability and protein translation. Messenger RNA regulatory elements typically reside within the 3' untranslated region (3'UTR) of the transcript and play a critical role in targeting specific mRNAs for posttranscriptional regulation through microRNA (miRNA) binding and adenylate- and uridylate-rich element RNA-binding proteins. In this review, we highlight the current advances in our understanding of the impact these RNA sequence elements have upon regulating PGE(2) levels. We also identify various RNA sequence elements consistently observed within the 3'UTRs of the genes involved in the PGE(2) pathway, indicating these binding sites for miRNAs and RNA-binding proteins to be central regulators of PGE(2) synthesis and function. These findings may provide a rationale for the development of new therapeutic approaches to control tumor growth and metastasis promoted by elevated PGE(2) levels.
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Affiliation(s)
- Ashleigh E. Moore
- Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
| | - Lisa E. Young
- Novartis Institutes for Biomedical Research, RNAi Therapeutics, Cambridge, MA, USA
| | - Dan A. Dixon
- Department of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
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28
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Greene ER, Huang S, Serhan CN, Panigrahy D. Regulation of inflammation in cancer by eicosanoids. Prostaglandins Other Lipid Mediat 2011; 96:27-36. [PMID: 21864702 PMCID: PMC4051344 DOI: 10.1016/j.prostaglandins.2011.08.004] [Citation(s) in RCA: 233] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Revised: 08/05/2011] [Accepted: 08/08/2011] [Indexed: 12/12/2022]
Abstract
Inflammation in the tumor microenvironment is now recognized as one of the hallmarks of cancer. Endogenously produced lipid autacoids, locally acting small molecule lipid mediators, play a central role in inflammation and tissue homeostasis, and have recently been implicated in cancer. A well-studied group of autacoid mediators that are the products of arachidonic acid metabolism include: the prostaglandins, leukotrienes, lipoxins and cytochrome P450 (CYP) derived bioactive products. These lipid mediators are collectively referred to as eicosanoids and are generated by distinct enzymatic systems initiated by cyclooxygenases (COX 1 and 2), lipoxygenases (5-LOX, 12-LOX, 15-LOXa, 15-LOXb), and cytochrome P450s, respectively. These pathways are the target of approved drugs for the treatment of inflammation, pain, asthma, allergies, and cardiovascular disorders. Beyond their potent anti-inflammatory and anti-cancer effects, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 specific inhibitors have been evaluated in both preclinical tumor models and clinical trials. Eicosanoid biosynthesis and actions can also be directly influenced by nutrients in the diet, as evidenced by the emerging role of omega-3 fatty acids in cancer prevention and treatment. Most research dedicated to using eicosanoids to inhibit tumor-associated inflammation has focused on the COX and LOX pathways. Novel experimental approaches that demonstrate the anti-tumor effects of inhibiting cancer-associated inflammation currently include: eicosanoid receptor antagonism, overexpression of eicosanoid metabolizing enzymes, and the use of endogenous anti-inflammatory lipid mediators. Here we review the actions of eicosanoids on inflammation in the context of tumorigenesis. Eicosanoids may represent a missing link between inflammation and cancer and thus could serve as therapeutic target(s) for inhibiting tumor growth.
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Affiliation(s)
- Emily R. Greene
- Vascular Biology Program, Children’s Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
- Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Sui Huang
- Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Canada
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.
| | - Dipak Panigrahy
- Vascular Biology Program, Children’s Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
- Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
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29
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Woodward DF, Jones RL, Narumiya S. International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev 2011; 63:471-538. [PMID: 21752876 DOI: 10.1124/pr.110.003517] [Citation(s) in RCA: 332] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
It is now more than 15 years since the molecular structures of the major prostanoid receptors were elucidated. Since then, substantial progress has been achieved with respect to distribution and function, signal transduction mechanisms, and the design of agonists and antagonists (http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=58). This review systematically details these advances. More recent developments in prostanoid receptor research are included. The DP(2) receptor, also termed CRTH2, has little structural resemblance to DP(1) and other receptors described in the original prostanoid receptor classification. DP(2) receptors are more closely related to chemoattractant receptors. Prostanoid receptors have also been found to heterodimerize with other prostanoid receptor subtypes and nonprostanoids. This may extend signal transduction pathways and create new ligand recognition sites: prostacyclin/thromboxane A(2) heterodimeric receptors for 8-epi-prostaglandin E(2), wild-type/alternative (alt4) heterodimers for the prostaglandin FP receptor for bimatoprost and the prostamides. It is anticipated that the 15 years of research progress described herein will lead to novel therapeutic entities.
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Affiliation(s)
- D F Woodward
- Dept. of Biological Sciences RD3-2B, Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612, USA.
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Takahashi T, Ogawa H, Izumi K, Uehara H. The soluble EP2 receptor FuEP2/Ex2 suppresses endometrial cancer cell growth in an orthotopic xenograft model in nude mice. Cancer Lett 2011; 306:67-75. [PMID: 21419570 DOI: 10.1016/j.canlet.2011.02.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Revised: 02/18/2011] [Accepted: 02/21/2011] [Indexed: 10/18/2022]
Abstract
Endometrial cancer is one of the most common gynecologic malignancies and many factors influence in its growth and development. As in many other types of cancer, prostaglandin E(2) (PGE(2)) is thought to be an accelerator of cell proliferation and endometrial cancer progression. In this study, we examined the effect of FuEP2/Ex2, a soluble decoy receptor for PGE(2) on growth of endometrial cancer cells. A stable transfectant expressing FuEP2/Ex2 was established from human endometrial cancer Ishikawa cells (Ish-FuEP2/Ex2). Ish-FuEP2/Ex2 cells expressed FuEP2/Ex2 mRNA and protein. Expression levels of E-prostanoid receptor 1 (EP1), EP2, EP3, EP4, and F-prostanoid receptor (FP) were almost the same in Ish-FuEP2/Ex2 and vector control cells. Growth rates of Ish-FuEP2/Ex2 under normal culture conditions were also similar to vector control cells, although PGE(2)-induced growth stimulation was completely inhibited in Ish-FuEP2/Ex2 or by Ish-FuEP2/Ex2 culture medium. Moreover, phosphorylation of extracellular signal-regulated kinase (ERK) and induction of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), cyclin D1, and c-fos mRNA by PGE(2) were not observed in Ish-FuEP2/Ex2 and Ish-FuEP2/Ex2 culture medium-treated vector control cells, although they were found when treated with prostaglandin F(2α). An orthotopic xenograft model in athymic nude mice revealed that Ish-FuEP2/Ex2-injected mice had significantly decreased mean tumor area. The proportion of Ki-67-positive cells in the tumor lesion was also significantly lower in Ish-FuEP2/Ex2-injected mice. These findings suggest that an EP-targeting strategy using FuEP2/Ex2 may be of use in the treatment of endometrial cancer.
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Affiliation(s)
- Tetsuyuki Takahashi
- Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
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31
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Shin VY, Jin HC, Ng EKO, Cho CH, Leung WK, Sung JJY, Chu KM. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro. Cancer Sci 2011; 102:926-33. [DOI: 10.1111/j.1349-7006.2011.01885.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Surh I, Rundhaug J, Pavone A, Mikulec C, Abel E, Fischer SM. Upregulation of the EP1 receptor for prostaglandin E2 promotes skin tumor progression. Mol Carcinog 2011; 50:458-68. [PMID: 21268127 DOI: 10.1002/mc.20730] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Revised: 11/08/2010] [Accepted: 11/29/2010] [Indexed: 11/08/2022]
Abstract
Prostaglandin E(2) (PGE(2) ) has been shown to promote the development of murine skin tumors. EP1 is 1 of the 4 PGE(2) G-protein-coupled membrane receptors expressed by murine keratinocytes. EP1 mRNA levels were increased ∼2-fold after topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) or exposure to ultraviolet (UV) light, as well as increased ∼3- to 12-fold in tumors induced by 7,12-dimethyl-benz[a]anthracene (DMBA) initiation/TPA promotion or by UV exposure. To determine the effect of EP1 levels on tumor development, we generated BK5.EP1 transgenic mice that overexpress EP1 in the basal layer of the epidermis. Skins of these mice were histologically indistinguishable from wild type (WT) mice and had similar levels of proliferation after TPA treatment. Using a DMBA/TPA carcinogenesis protocol, BK5.EP1 mice had a reduced tumor multiplicity compared to WT mice, likely due to the observed down-regulation of protein kinase C (PKC). However, the BK5.EP1 mice had an ∼8-fold higher papilloma to carcinoma conversion rate. When DMBA/anthralin was used, BK5.EP1 mice produced more tumors than WT mice, as well as a ninefold increase in carcinomas, indicating that the tumor response is dependent on the type of tumor promoter agent used. Additionally, although almost undetectable in WT mice, cyclooxygenase-2 (COX-2) was expressed in the untreated epidermis of BK5.EP1 mice. While TPA highly induced COX-2 in WT mice, COX-2 expression in the BK5.EP1 mice did not change after TPA treatment; PGE(2) levels were likewise affected. These data indicate that EP1 is more important in tumor progression than in tumor promotion and that it indirectly regulates COX-2 expression.
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Affiliation(s)
- Inok Surh
- The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA
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33
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Ma X, Kundu N, Ioffe OB, Goloubeva O, Konger R, Baquet C, Gimotty P, Reader J, Fulton AM. Prostaglandin E receptor EP1 suppresses breast cancer metastasis and is linked to survival differences and cancer disparities. Mol Cancer Res 2010; 8:1310-8. [PMID: 20858737 DOI: 10.1158/1541-7786.mcr-10-0003] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cyclooxygenase-2 is frequently overexpressed and associated with poor prognosis in breast cancer. The cyclooxygenase-2 product prostaglandin E(2) elicits cellular responses through four G-protein-coupled receptors, designated EP1 to EP4, coupled to distinct intracellular signaling pathways. EP4, expressed on malignant breast cells, promotes metastasis; however, a role for EP1 in metastasis has not been investigated. Using a murine model of metastatic breast cancer, we now show that pharmacologic antagonism of EP1 with SC19220 or AH6809 promoted lung colonization of mammary tumor cells by 3.7- to 5.4-fold. Likewise, reducing EP1 gene expression by shRNA also increased metastatic capacity relative to cells transfected with nonsilencing vector but did not affect the size of transplanted tumors. Examination of invasive ductal carcinomas by immunohistochemistry shows that EP1 was detected in both the cytoplasm and nucleus of benign ducts as well as malignant cells in some samples, but was absent or limited to either the nucleus or cytoplasm in other malignant samples. Overall survival for women with tumors that were negative for nuclear EP1 was significantly worse than for women with EP1 expression (P = 0.008). There was no difference in survival for women with differences in cytoplasmic EP1 expression (P = 0.46). Comparing EP1 mRNA in breast tumors from African American and European American women revealed that many more African American breast tumors lacked detectable EP1 mRNA (P = 0.04). These studies support the hypothesis that EP1 functions as a metastasis suppressor and that loss of nuclear EP1 is associated with poorer overall survival and may contribute to disparities in outcome in different populations.
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Affiliation(s)
- Xinrong Ma
- University of Maryland, Greenebaum Cancer Center, Baltimore, MD 21201, USA
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34
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Abstract
Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids that have been implicated in various pathological processes, such as inflammation and cancer. This Review highlights our understanding of the intricate roles of eicosanoids in epithelial-derived tumours and their microenvironment. The knowledge of how these lipids orchestrate the complex interactions between transformed epithelial cells and the surrounding stromal cells is crucial for understanding tumour evolution, progression and metastasis. Understanding the molecular mechanisms underlying the role of prostaglandins and other eicosanoids in cancer progression will help to develop more effective cancer chemopreventive and/or therapeutic agents.
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Affiliation(s)
- Dingzhi Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA
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35
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Kaneshiro T, Okumura M, Maalouf S, Uflacker A, Maruyama T, Kawamori T. Inhibition of prostaglandin E(2) signaling through the EP(1) receptor does not affect prostacyclin production in human endothelial cells. Prostaglandins Other Lipid Mediat 2009; 90:31-6. [PMID: 19647091 PMCID: PMC2767438 DOI: 10.1016/j.prostaglandins.2009.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Revised: 07/20/2009] [Accepted: 07/21/2009] [Indexed: 01/06/2023]
Abstract
Accumulating evidence suggests that cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) may play an important role in colon carcinogenesis. Thus, blockage of this pathway may be a suitable strategy for colon cancer chemoprevention. Recent clinical studies suggest that COX-2 inhibitors cause adverse cardiovascular effects due to prostacyclin (PGI(2)) inhibition. To test our hypothesis that inhibition of PGE(2) signaling through E-prostanoid (EP) receptors may offer a safer cardiovascular profile than COX-2 inhibition, we analyzed expression of 6-keto PGF(1alpha), a hydrated form of PGI(2) and PGI(2) synthase, which was stimulated with cytokines in human umbilical vein endothelial cells (HUVECs) treated with the EP(1) receptor antagonist ONO-8711 or the COX-2 inhibitor celecoxib. ONO-8711 did not inhibit both 6-keto PGF(1alpha) production and PGIS expression, whereas celecoxib did in HUVECs. ONO-8711 also inhibited cytokine-induced tissue factor expression in HUVECs. These results suggest that ONO-8711 may be a safer chemopreventive agent with respect to cardiovascular events.
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Affiliation(s)
- Tatsuya Kaneshiro
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425 USA
| | - Masae Okumura
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425 USA
| | - Samer Maalouf
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425 USA
| | - Andre Uflacker
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425 USA
| | | | - Toshihiko Kawamori
- Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425 USA
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Kundu N, Ma X, Holt D, Goloubeva O, Ostrand-Rosenberg S, Fulton AM. Antagonism of the prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res Treat 2008; 117:235-42. [PMID: 18792778 DOI: 10.1007/s10549-008-0180-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Accepted: 09/02/2008] [Indexed: 12/31/2022]
Abstract
Cyclooxygenase-2 (COX-2) is associated with aggressive breast cancers. The COX-2 product prostaglandin E(2) (PGE(2)) acts through four G-protein-coupled receptors designated EP1-4. Malignant and immortalized normal mammary epithelial cell lines express all four EP. The EP4 antagonist AH23848 reduced the ability of tumor cells to colonize the lungs or to spontaneously metastasize from the mammary gland. EP4 gene silencing by shRNA also reduced the ability of mammary tumor cells to metastasize. Metastasis inhibition was lost in mice lacking either functional Natural Killer (NK) cells or interferon-gamma. EP4 antagonism inhibited MHC class I expression resulting in enhanced ability of NK cells to lyse mammary tumor target cells. These studies support the hypothesis that EP4 receptor antagonists reduce metastatic potential by facilitating NK-mediated tumor cell killing and that therapeutic targeting of EP4 may be an alternative approach to the use of COX inhibitors to limit metastatic disease.
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Affiliation(s)
- Namita Kundu
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Breinig M, Rieker R, Eiteneuer E, Wertenbruch T, Haugg AM, Helmke BM, Schirmacher P, Kern MA. Differential expression of E-prostanoid receptors in human hepatocellular carcinoma. Int J Cancer 2008; 122:547-57. [PMID: 17918156 DOI: 10.1002/ijc.23098] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recent studies have shown that inhibition of cyclooxygenases (e.g. COX-2) exerts antitumorigenic effects on hepatocellular carcinomas (HCCs), which are to a significant extent due to the abrogation of PGE(2) synthesis. PGE(2) acts via differentially regulated prostaglandin receptors (EP(1-4)). Our study was designed to investigate the expression pattern of EP-receptors in HCCs and to evaluate the therapeutic potential of selective EP-receptor antagonists. Using tissue microarrays including a total of 14 control livers, 17 liver cirrhoses, 22 premalignant dysplastic nodules (DNs) and 162 HCCs with different histological grades, the expression of COX-2, mPGES-1 and -2 and EP(1-4)-receptors was analyzed. Western immunoblot analyses were performed to confirm the expression in HCC cell lines. The effects of EP(1-4)-receptor antagonism on cell viability and apoptosis were investigated using MTT-assays and FACS-analyses, respectively. COX-2, mPGES-1 and -2 and EP(1-4)-receptors were expressed in all HCC tissues. COX-2 expression was highest in DNs and declined with loss of HCC-differentiation. With respect to COX-2 expression, a converse expression of EP(1-3) -receptors and mPGES-1 and -2 was found in DNs compared to HCCs. Selectively antagonizing EP(1)- and EP(3)-receptors reduced the viability of HCC cells in a dose-dependent manner, which was associated with apoptosis induction. Our results suggest a differential regulation of EP-receptor subtype expression with dedifferentiation of HCCs in which a converse expression pattern for COX-2 in comparison to EP(1-3)-receptors occurs. Of clinical interest, selectively antagonizing EP(1)- and EP(3)-receptors may provide a novel systemic therapeutic approach to the treatment of HCCs.
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Affiliation(s)
- Marco Breinig
- Department of General Pathology, University Hospital, 69120 Heidelberg, Germany
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38
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Thorat MA, Morimiya A, Mehrotra S, Konger R, Badve SS. Prostanoid receptor EP1 expression in breast cancer. Mod Pathol 2008; 21:15-21. [PMID: 17906615 DOI: 10.1038/modpathol.3800970] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P=0.032) and inversely with node positivity (P=0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P=0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Blotting, Western
- Breast Neoplasms/chemistry
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Cell Nucleus/chemistry
- Cyclooxygenase 2/analysis
- Cytoplasm/chemistry
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immunohistochemistry
- Middle Aged
- Neoplasm Staging
- Prognosis
- RNA, Messenger/analysis
- Receptor, ErbB-2/analysis
- Receptors, Estrogen/analysis
- Receptors, Progesterone/analysis
- Receptors, Prostaglandin E/analysis
- Receptors, Prostaglandin E/genetics
- Receptors, Prostaglandin E, EP1 Subtype
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Mangesh A Thorat
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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39
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Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 2007; 67:4507-13. [PMID: 17483367 DOI: 10.1158/0008-5472.can-06-4174] [Citation(s) in RCA: 582] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-1beta, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1(+)CD11b(+) MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor-bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population.
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Affiliation(s)
- Pratima Sinha
- Department of Biological Sciences, University of Maryland Baltimore County, University of Maryland, Baltimore, Maryland 21250, USA
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40
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Hall A, Atkinson S, Brown SH, Chessell IP, Chowdhury A, Giblin GMP, Goldsmith P, Healy MP, Jandu KS, Johnson MR, Michel AD, Naylor A, Sweeting JA. Discovery of novel, non-acidic 1,5-biaryl pyrrole EP1 receptor antagonists. Bioorg Med Chem Lett 2007; 17:1200-5. [PMID: 17196385 DOI: 10.1016/j.bmcl.2006.12.021] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2006] [Revised: 12/07/2006] [Accepted: 12/08/2006] [Indexed: 11/27/2022]
Abstract
Replacement of the carboxylic acid group in a series of previously described 1,5-biaryl pyrrole EP1 receptor antagonists led to the discovery of various novel non-acidic antagonists. Several analogues displayed high binding affinity and high binding efficiency indices.
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Affiliation(s)
- Adrian Hall
- Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
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41
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Miyata Y, Kanda S, Maruta S, Matsuo T, Sakai H, Hayashi T, Kanetake H. Relationship between prostaglandin E2 receptors and clinicopathologic features in human prostate cancer tissue. Urology 2007; 68:1360-5. [PMID: 17169665 DOI: 10.1016/j.urology.2006.09.035] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2005] [Revised: 06/12/2006] [Accepted: 09/14/2006] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Prostaglandin E2 is involved in the carcinogenic process and malignant aggressiveness. These effects are mediated through binding to four specific type E prostanoid (EP) receptors (EP1R to EP4R). Although EPRs are overexpressed in a variety of cancers, their expression pattern varies among different cancer types. The aim of this study was to clarify the clinical significance of EPRs in prostate cancer. METHODS We examined the expression of each EPR in 122 prostate cancer tissue samples by immunohistochemistry. We also investigated the relationship between EPRs and cancer cell proliferation. RESULTS The rate of immunopositivity for EP1R in cancer cells (36.3% +/- 14.3%) was significantly greater (P < 0.01) than in nontumor glands (7.1% +/- 4.8%) and correlated positively with the Gleason score (P < 0.01), T stage (P < 0.01), N stage (P = 0.03), M stage (P < 0.01), and cancer cell proliferation (r = 0.35, P < 0.01). The EP2R expression in cancer cells (38.9% +/- 11.6%) was significantly greater (P < 0.01) than in nontumor glands (30.6% +/- 8.6%), and correlated with cancer cell proliferation (P < 0.01). The EP4R expression in cancer cells was also significantly greater (P < 0.01) than in nontumor glands. However, the expression of EP2R and EP4R did not correlate with the clinicopathologic features and EP3R expression was not associated with any parameters. CONCLUSIONS Our results have indicated that EP1R, EP2R, and EP4R are associated with prostate carcinogenesis. In particular, the EP1R seems to play an important role in malignant aggressiveness and tumor development in patients with prostate cancer.
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Affiliation(s)
- Yasuyoshi Miyata
- Department of Urology, Nagasaki University School of Medicine, Nagasaki, Japan.
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42
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Al-Waili NS, Saloom KY, Al-Waili T, Al-Waili A, Al-Waili H. Modulation of prostaglandin activity, part 1: prostaglandin inhibition in the management of nonrheumatologic diseases: immunologic and hematologic aspects. Adv Ther 2007; 24:189-222. [PMID: 17526477 DOI: 10.1007/bf02850008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prostaglandins (PGs) are active biologic substances that are involved in a wide range of physiologic processes; when their production is out of balance, they are factors in the pathogenesis of illness. Modulation of PGs by inhibition or stimulation is promising for the management of various conditions. PG inhibitors are widely used to relieve pain and inflammation in patients with rheumatologic disease. Interest in the use of PG inhibitors to prevent cancer and cardiovascular events is growing. More than 27 y ago, investigators found that PG depresses antibody production in vivo; reduces serum iron, hemoglobin, and leukoid series in bone marrow during acute and chronic blood loss; reduces albumin during antigenic stimulation; suppresses hypercalcemia after bleeding; and reduces fasting blood sugar and hyperglycemia after ether anesthesia and bleeding. Chronic conditions that produce large quantities of PGs are associated with immunosuppression and secondary anemia. Investigators in the present study hypothesized (1) that the overproduction of PGs is responsible for immunosuppression and secondary anemia in conditions associated with increased PG synthesis, such as pathologic inflammation, malignancy, trauma, and injury, and (2) that PG inhibitors reverse immunosuppression and secondary anemia, thereby enhancing the immune response. This is supported by many reports that show the immunosuppressive effects of PGs and their role in the immunosuppression associated with pathologic inflammation, burns, trauma, and tumors. Inhibition of PGs can be achieved through the use of synthetic medicines and natural products. This article reviews the effects of PGs and inhibition of increased synthesis of PGs on the lymphoid system, hematologic indices, and bone marrow elements in trauma, injury, burns, and tumors. The Medline database (1966-2006) was used in this study. Investigators in the present study and others have provided evidence that shows the involvement of PGs in immunosuppression and secondary anemia, as well as the efficacy of inhibited overproduction of PGs in many pathologic conditions other than rheumatologic disease.
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Affiliation(s)
- Noori S Al-Waili
- Al-Waili's Charitable Foundation for Science and Trading, New York City, NY, USA.
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43
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Abstract
It is well established that high cyclooxygenase-2 (COX-2) expression contributes to the aggressive behavior of breast and other malignancies. Due to concerns regarding the safety of long-term use of COX-2 inhibitors as well as a desire to seek more effective alternatives to prevent and treat metastatic disease, we tested the hypothesis that inhibition of downstream signaling by the COX-2 product prostaglandin E(2) (PGE(2)) would be as effective as inhibiting global prostaglandin synthesis. PGE(2) acts through four G-protein-coupled receptors designated EP1-4. Here, we summarize data from many laboratories regarding the role of individual E-series of prostaglandin (EP) receptors on cancer behavior and we discuss our own recent findings that antagonists of the PGE receptor subtype 4, EP4, inhibit experimental metastasis in a murine model of hormone-resistant, metastatic breast cancer. These initial results indicate that selective targeting of individual EP receptors should be investigated as an approach to exploit the high COX-2 activity in many epithelial malignancies.
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Affiliation(s)
- Amy M Fulton
- Department of Pathology and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
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44
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Piazuelo E, Jiménez P, Strunk M, Santander S, García A, Esteva F, Lanas A. Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus. Prostaglandins Other Lipid Mediat 2006; 81:150-61. [PMID: 17085323 DOI: 10.1016/j.prostaglandins.2006.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Revised: 06/09/2006] [Accepted: 09/04/2006] [Indexed: 11/20/2022]
Abstract
Accumulating evidence suggests that COX-2-derived prostaglandin E(2) (PGE(2)) plays an important role in esophageal adenocarcinogenesis. Recently, PGE(2) receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE(2) signals in esophageal adenocarcinoma, we investigated the role of EP receptors using a human Barrett's-derived esophageal adenocarcinoma cell line (OE33). OE33 cells expressed COX-1, COX-2, EP(1), EP(2) and EP(4) but not EP(3) receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP(3) downregulation. Endogenous PGE(2) production was mainly due to COX-2, since this was significantly suppressed with COX-2 inhibitors (NS-398 and SC-58125), but not COX-1 inhibitors (SC-560). Cell proliferation ((3)H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP(1) antagonist SC-51322, AH6809 (EP(1)/EP(2) antagonist), and the EP(4) antagonist AH23848B, but was not affected by exogenous PGE(2). However, treatment with the selective EP(2) agonist Butaprost or 16,16-dimethylPGE(2) significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE(2) on migration was attenuated when cells were first treated with EP(1) and EP(4) antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma.
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Affiliation(s)
- Elena Piazuelo
- Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
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45
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Prosperi JR, Robertson FM. Cyclooxygenase-2 directly regulates gene expression of P450 Cyp19 aromatase promoter regions pII, pI.3 and pI.7 and estradiol production in human breast tumor cells. Prostaglandins Other Lipid Mediat 2006; 81:55-70. [PMID: 16997132 DOI: 10.1016/j.prostaglandins.2006.07.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2006] [Revised: 07/25/2006] [Accepted: 07/31/2006] [Indexed: 11/28/2022]
Abstract
The present studies evaluated the direct effects of the presence of human cyclooxygenase-2 (Cox-2) on gene expression of specific promoter regions of the P450 Cyp19 enzyme aromatase enzyme and its product, estradiol, in Cox-2 null estrogen-dependent MCF-7 breast tumor cells and in a stable clone of MCF-7 cells containing transfected Cox-2 cDNA, designated as MCF-7/Cox-2 Clone 10. Clone 10 human breast tumor cells have significantly increased gene expression of total mRNA of the P450 Cyp19 enzyme aromatase, with high levels of gene expression of specific aromatase promoter (p) regions pII, pI.3, and p1.7, with no significant change in mRNA levels of p1.4. Clone 10 human breast tumor cells produced significantly increased amounts of both prostaglandin E2 (PGE2) derived from Cox-2 enzyme activity and estradiol derived from aromatase enzyme activity (p<0.01), compared to MCF-7/vector control cells. The greatest inhibition of PGE2 or estradiol production was observed by the combination of the selective Cox-2 inhibitor celecoxib (25 microM) and the aromatase inhibitor, formestane (10nM) (p<0.01). The greatest anti-proliferative effect in Cox-2 null MCF-7/vector control cells was observed with the combination of 25 microM celecoxib and 10nM formestane but not with 10 microM celecoxib, suggesting that there are Cox-2-independent mechanisms involved in the anti-proliferative effect of this agent at doses greater than 10 microM. Celecoxib (25 microM) also significantly inhibited proliferation of MCF-7/Cox-2 Clone 10 human breast tumor cells, with no further anti-proliferative activity with the addition of 10 nM formestane observed at either 24 or 48 h of treatment. These studies demonstrate that Cox-2 directly regulates gene expression of specific aromatase promoter regions and regulates aromatase enzyme activity. Agents that inhibit Cox-2 or block the biological effects of PGE2 may be useful in significantly limiting aromatase activity and proliferation of human breast tumor cells regardless of the presence of Cox-2. In addition, the unique human breast tumor cell model used in these studies may be a useful tool in identifying the spectrum of activities of agents that block the biological effects of PGE2 and estradiol.
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Affiliation(s)
- Jenifer R Prosperi
- Department of Molecular Virology, Immunology, and Medical Genetics, The Integrated Biomedical Science Graduate Program, The Ohio State University College of Medicine, 2184 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA
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46
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Tober KL, Thomas-Ahner JM, Kusewitt DF, Oberyszyn TM. Effects of UVB on E prostanoid receptor expression in murine skin. J Invest Dermatol 2006; 127:214-21. [PMID: 16917495 DOI: 10.1038/sj.jid.5700502] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Prostaglandin E2 (PGE2) upregulation in response to UV light exposure is a significant factor in the development of non-melanoma skin cancer. It is known that PGE2 signals via the E prostanoid receptors, EP1-4, but the role that each receptor plays in skin carcinogenesis is unclear. Immunohistochemical analysis of EP receptor staining in unirradiated and UVB-exposed SKH-1 mouse skin demonstrated the localization of EP1 and EP2 to the plasma membrane of differentiated epidermal keratinocytes. In contrast, the EP3 receptor localized to the basal layer of the epidermis in unirradiated skin and throughout the epidermis in UVB-exposed skin. In unirradiated skin, cytoplasmic EP4 staining was seen throughout the epidermis, in dermal leukocytes, and in vascular endothelium. However, UVB exposure resulted in relocalization of the EP4 receptor to the plasma membrane of keratinocytes, with no change in the dermal staining pattern. In tumors isolated from UVB-exposed mice, EP1 and EP2 staining was detected in the more differentiated cells surrounding keratin pearls, whereas EP3 and EP4 were detectable throughout the tumors. Differential expression of the EP receptors suggests that each receptor may play a distinct role in skin tumor development.
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MESH Headings
- Animals
- Female
- Immunohistochemistry
- Mice
- Mice, Hairless
- Neoplasms, Radiation-Induced/chemistry
- Neoplasms, Radiation-Induced/drug therapy
- RNA, Messenger/analysis
- Receptors, Prostaglandin E/analysis
- Receptors, Prostaglandin E/antagonists & inhibitors
- Receptors, Prostaglandin E/genetics
- Receptors, Prostaglandin E/physiology
- Receptors, Prostaglandin E, EP1 Subtype
- Receptors, Prostaglandin E, EP2 Subtype
- Receptors, Prostaglandin E, EP3 Subtype
- Receptors, Prostaglandin E, EP4 Subtype
- Skin/chemistry
- Skin/radiation effects
- Skin Neoplasms/chemistry
- Skin Neoplasms/drug therapy
- Ultraviolet Rays
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Affiliation(s)
- Kathleen L Tober
- Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA
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47
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Hall A, Atkinson S, Brown SH, Chessell IP, Chowdhury A, Clayton NM, Coleman T, Giblin GMP, Gleave RJ, Hammond B, Healy MP, Johnson MR, Michel AD, Naylor A, Novelli R, Spalding DJ, Tang SP. Structure–activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists. Bioorg Med Chem Lett 2006; 16:3657-62. [PMID: 16697196 DOI: 10.1016/j.bmcl.2006.04.073] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2006] [Accepted: 04/23/2006] [Indexed: 11/20/2022]
Abstract
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
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Affiliation(s)
- Adrian Hall
- Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
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48
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Chell S, Kaidi A, Kadi A, Williams AC, Paraskeva C. Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. Biochim Biophys Acta Rev Cancer 2006; 1766:104-19. [PMID: 16859832 DOI: 10.1016/j.bbcan.2006.05.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2006] [Revised: 05/18/2006] [Accepted: 05/18/2006] [Indexed: 12/25/2022]
Abstract
Colorectal cancer is a major cause of mortality and whilst up to 80% of sporadic colorectal tumours are considered preventable, trends toward increasing obesity suggest the potential for a further increase in its worldwide incidence. Novel methods of colorectal cancer prevention and therapy are therefore of considerable importance. Non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive against colorectal cancer, mainly through their inhibitory effects on the cyclooxygenase isoform COX-2. COX enzymes represent the committed step in prostaglandin biosynthesis and it is predominantly increased COX-2-mediated prostaglandin-E2 (PGE2) production that has a strong association with colorectal neoplasia, by promoting cell survival, cell growth, migration, invasion and angiogenesis. COX-1 and COX-2 inhibition by traditional NSAIDs (for example, aspirin) although chemopreventive have some side effects due to the role of COX-1 in maintaining the integrity of the gastric mucosa. Interestingly, the use of COX-2 selective NSAIDs has also shown promise in the prevention/treatment of colorectal cancer while having a reduced impact on the gastric mucosa. However, the prolonged use of high dose COX-2 selective inhibitors is associated with a risk of cardiovascular side effects. Whilst COX-2 inhibitors may still represent viable adjuvants to current colorectal cancer therapy, there is an urgent need to further our understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and hence identify safer, more effective strategies for the prevention of colorectal cancer. In particular, PGE2 synthases and E-prostanoid receptors (EP1-4) have recently attracted considerable interest in this area. It is hoped that at the appropriate stage, selective (and possibly combinatorial) inhibition of the synthesis and signalling of those prostaglandins most highly associated with colorectal tumorigenesis, such as PGE2, may have advantages over COX-2 selective inhibition and therefore represent more suitable targets for long-term chemoprevention. Furthermore, as COX-2 is found to be overexpressed in cancers such as breast, gastric, lung and pancreatic, these investigations may also have broad implications for the prevention/treatment of a number of other malignancies.
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Affiliation(s)
- Simon Chell
- Cancer Research UK, Colorectal Tumour Biology Group, Department of Cellular and Molecular Medicine, University Walk, The Medical School, Bristol University, Bristol BS91SB, UK
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49
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Ma X, Kundu N, Rifat S, Walser T, Fulton AM. Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res 2006; 66:2923-7. [PMID: 16540639 DOI: 10.1158/0008-5472.can-05-4348] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cyclooxygenase-2 (COX-2) expression in epithelial tumors is frequently associated with a poor prognosis. In a murine model of metastatic breast cancer, we showed that COX-2 inhibition is associated with decreased metastatic capacity. The COX-2 product, prostaglandin E(2) (PGE(2)), acts through a family of G protein-coupled receptors designated EP1-4 that mediate intracellular signaling by multiple pathways. We characterized EP receptor expression on three murine mammary tumor cell lines and show that all four EP isoforms were detected in each cell. Stimulation of cells with either PGE(2) or the selective EP4/EP2 agonist PGE(1)-OH resulted in increased intracellular cyclic AMP and this response was inhibited with either EP2 or EP4 antagonists. Nothing is known about the function of EP receptors in tumor metastasis. We tested the hypothesis that the prevention of EP receptor signaling would, like inhibition of PGE(2) synthesis, inhibit tumor metastasis. Our results show for the first time that antagonism of the EP4 receptor with either AH23848 or ONO-AE3-208 reduced metastasis as compared with vehicle-treated controls. The therapeutic effect was comparable to that observed with the dual COX-1/COX-2 inhibitor indomethacin. EP3 antagonism had no effect on tumor metastasis. Mammary tumor cells migrated in vitro in response to PGE(2) and this chemotactic response was blocked by EP receptor antagonists. Likewise, the proliferation of tumor cells was also directly inhibited by antagonists of either EP4 or EP1/EP2. These studies support the hypothesis that EP receptor antagonists may be an alternative approach to the use of COX inhibitors to prevent tumor metastasis.
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Affiliation(s)
- Xinrong Ma
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
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50
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Hall A, Bit RA, Brown SH, Chaignot HM, Chessell IP, Coleman T, Giblin GMP, Hurst DN, Kilford IR, Lewell XQ, Michel AD, Mohamed S, Naylor A, Novelli R, Skinner L, Spalding DJ, Tang SP, Wilson RJ. Discovery of novel biaryl heterocyclic EP1 receptor antagonists. Bioorg Med Chem Lett 2006; 16:2666-71. [PMID: 16503138 DOI: 10.1016/j.bmcl.2006.02.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2006] [Revised: 02/08/2006] [Accepted: 02/09/2006] [Indexed: 11/17/2022]
Abstract
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
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Affiliation(s)
- Adrian Hall
- Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
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