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Chen W, Huang Y, Li W, Fan G, Tang Y, Zhao W, Chen K, Chen Z, Zhou K, Li Z, Zhang H. The potential of pomegranate peel supplementation in Yellow-feathered broilers: effects on growth performance, serum biochemistry, antioxidant capacity, intestinal health, intestinal microbiota, and duodenal mucosal metabolites. Poult Sci 2025; 104:104983. [PMID: 40058007 PMCID: PMC11930591 DOI: 10.1016/j.psj.2025.104983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/24/2025] [Accepted: 03/03/2025] [Indexed: 03/28/2025] Open
Abstract
This study aimed to investigate the effects of dietary supplementation with pomegranate peel powder (PP) on the growth performance, serum biochemistry, antioxidant capacity, intestinal microbiota, and duodenal mucosal metabolites of yellow-feathered broilers. A total of 360 yellow-feathered broilers were randomly divided into three groups, with their diets supplemented with different levels of PP (0, 1, and 4 g/kg) for 42 days. Dietary supplementation with PP significantly increased the average body weight and average daily gain of yellow-feathered broilers during the periods of 1-21 and 22-42 days, while reducing the feed conversion ratio (p < 0.05). It also decreased the serum levels of aspartate aminotransferase, alanine aminotransferase, creatinine, and uric acid, increased the activities of glutathione peroxidase and superoxide dismutase, and reduced malondialdehyde content in the serum, liver, and intestinal mucosa (p < 0.05). Furthermore, PP supplementation promoted the mRNA expression of farnesoid X receptor, peroxisome proliferator-activated receptor alpha, fatty acid-binding protein 4, epidermal growth factor/epidermal growth factor receptor, and B-cell lymphoma 2, while decreasing the mRNA expression of caspase-1 and interleukin-1 beta (p < 0.05). Regarding mucosal metabolites, PP supplementation increased the contents of polyunsaturated fatty acids (cis-11-eicosenoic acid, cis-13,16-docosadienoic acid, and cis-11,14-eicosadienoic acid), prostaglandin E2/G2, and secondary bile acids (apocholic, hyodeoxycholic, 7-ketodeoxycholic, and omega-muricholic acids) in the mucosa (p < 0.05). In terms of cecal microbiota, PP supplementation increased the β-diversity index (p < 0.05), elevated the relative abundances of Bacteroidota, Alistipes, Bacilli, and Actinobacteriota, and reduced the relative abundances of Clostridia and Gammaproteobacteria (p < 0.05). In conclusion, dietary supplementation of PP can improve intestinal health and growth performance of yellow-feathered broilers by regulating the composition of the gut microbiota.
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Affiliation(s)
- Wang Chen
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Yurong Huang
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Wenlong Li
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Gao Fan
- Wen's Food Group, No. 9, North Dongdi Road, Xincheng Town, Yunfu, Guangdong 527400, China.
| | - Yanfang Tang
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Weiru Zhao
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Kexin Chen
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Zifan Chen
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
| | - Keyue Zhou
- Wen's Food Group, No. 9, North Dongdi Road, Xincheng Town, Yunfu, Guangdong 527400, China.
| | - Zhaoyao Li
- Wen's Food Group, No. 9, North Dongdi Road, Xincheng Town, Yunfu, Guangdong 527400, China; College of Veterinary Medicine, South China Agricultural University, No. 483, Wushan Road, Tianhe District, Guangzhou, Guangdong, 510642, China.
| | - Huihua Zhang
- School of Animal Science and Technology, Foshan University, No. 33 Guangyun Road, Shishan Town, Nanhai District, Foshan, Guangdong 528000, China.
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Filippelli A, Ciccone V, Del Gaudio C, Simonis V, Frosini M, Tusa I, Menconi A, Rovida E, Donnini S. ERK5 mediates pro-tumorigenic phenotype in non-small lung cancer cells induced by PGE2. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119810. [PMID: 39128596 DOI: 10.1016/j.bbamcr.2024.119810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 07/25/2024] [Accepted: 08/04/2024] [Indexed: 08/13/2024]
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) constituting approximately 84 % of all lung cancer cases. The role of inflammation in the initiation and progression of NSCLC tumors has been the focus of extensive research. Among the various inflammatory mediators, prostaglandin E2 (PGE2) plays a pivotal role in promoting the aggressiveness of epithelial tumors through multiple mechanisms, including the stimulation of growth, evasion of apoptosis, invasion, and induction of angiogenesis. The Extracellular signal-Regulated Kinase 5 (ERK5), the last discovered member among conventional mitogen-activated protein kinases (MAPK), is implicated in cancer-associated inflammation. In this study, we explored whether ERK5 is involved in the process of tumorigenesis induced by PGE2. Using A549 and PC9 NSCLC cell lines, we found that PGE2 triggers the activation of ERK5 via the EP1 receptor. Moreover, both genetic and pharmacological inhibition of ERK5 reduced PGE2-induced proliferation, migration, invasion and stemness of A549 and PC9 cells, indicating that ERK5 plays a critical role in PGE2-induced tumorigenesis. In summary, our study underscores the pivotal role of the PGE2/EP1/ERK5 axis in driving the malignancy of NSCLC cells in vitro. Targeting this axis holds promise as a potential avenue for developing novel therapeutic strategies aimed at controlling the advancement of NSCLC.
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Affiliation(s)
| | - Valerio Ciccone
- Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Cinzia Del Gaudio
- Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Vittoria Simonis
- Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Maria Frosini
- Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Ignazia Tusa
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Alessio Menconi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Elisabetta Rovida
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy.
| | - Sandra Donnini
- Department of Life Sciences, University of Siena, 53100 Siena, Italy.
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Ansari SS, Dillard ME, Zhang Y, Austria MA, Boatwright N, Shelton EL, Stewart DP, Johnson A, Wang CE, Young BM, Rankovic Z, Hansen BS, Pruett-Miller SM, Carisey AF, Schuetz JD, Robinson CG, Ogden SK. Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length. J Cell Biol 2024; 223:e202306002. [PMID: 38856684 PMCID: PMC11166601 DOI: 10.1083/jcb.202306002] [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: 06/01/2023] [Revised: 04/03/2024] [Accepted: 05/24/2024] [Indexed: 06/11/2024] Open
Abstract
Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness. Mechanisms by which ciliary robustness is ensured in SHH-stimulated cells are not yet known. Herein, we reveal a crosstalk circuit induced by SHH activation of Phospholipase A2α that drives ciliary E-type prostanoid receptor 4 (EP4) signaling to ensure PC function and stabilize ciliary length. We demonstrate that blockade of SHH-EP4 crosstalk destabilizes PC cyclic AMP (cAMP) equilibrium, slows ciliary transport, reduces ciliary length, and attenuates SHH pathway induction. Accordingly, Ep4-/- mice display shortened neuroepithelial PC and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates coordination between distinct ciliary receptors to maintain PC function and length homeostasis for robust downstream signaling.
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Affiliation(s)
- Shariq S. Ansari
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Miriam E. Dillard
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Yan Zhang
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Mary Ashley Austria
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Rhodes College Summer Plus Program, Memphis, TN, USA
| | - Naoko Boatwright
- Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt and Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Elaine L. Shelton
- Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt and Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Daniel P. Stewart
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Amanda Johnson
- Cell and Tissue Imaging Center, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Christina E. Wang
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Brandon M. Young
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Zoran Rankovic
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Baranda S. Hansen
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Shondra M. Pruett-Miller
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Alexandre F. Carisey
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - John D. Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Camenzind G. Robinson
- Cell and Tissue Imaging Center, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Stacey K. Ogden
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
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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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Sorrin AJ, Liu C, Cicalo J, Reader J, Najafali D, Zhang Y, Roque DM, Huang HC. Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro. Cancers (Basel) 2021; 13:5259. [PMID: 34771424 PMCID: PMC8582354 DOI: 10.3390/cancers13215259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/05/2021] [Accepted: 10/10/2021] [Indexed: 12/11/2022] Open
Abstract
The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are "photodynamically primed", or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.
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Affiliation(s)
- Aaron J. Sorrin
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Cindy Liu
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Julia Cicalo
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Jocelyn Reader
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (J.R.); (D.M.R.)
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
| | - Daniel Najafali
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
| | - Yuji Zhang
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Dana M. Roque
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (J.R.); (D.M.R.)
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (A.J.S.); (C.L.); (J.C.); (D.N.)
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA;
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Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro. Int J Mol Sci 2021; 22:ijms22094297. [PMID: 33919029 PMCID: PMC8122446 DOI: 10.3390/ijms22094297] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/02/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.
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EP4 as a Negative Prognostic Factor in Patients with Vulvar Cancer. Cancers (Basel) 2021; 13:cancers13061410. [PMID: 33808776 DOI: 10.3390/cancers13061410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/01/2021] [Accepted: 03/17/2021] [Indexed: 01/10/2023] Open
Abstract
New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients' survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2'-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma.
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EP4 receptor as a novel promising therapeutic target in colon cancer. Pathol Res Pract 2020; 216:153247. [PMID: 33190014 DOI: 10.1016/j.prp.2020.153247] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/06/2020] [Accepted: 10/08/2020] [Indexed: 01/17/2023]
Abstract
The most prevalent malignancy that can occur in the gastrointestinal tract is colon cancer. The current treatment options for colon cancer patients include chemotherapy, surgery, radiotherapy, immunotherapy, and targeted therapy. Although the chance of curing the disease in the early stages is high, there is no cure for almost all patients with advanced and metastatic disease. It has been found that over-activation of cyclooxygenase 2 (COX-2), followed by the production of prostaglandin E2 (PGE2) in patients with colon cancer are significantly increased. The tumorigenic function of COX-2 is mainly due to its role in the production of PGE2. PGE2, as a main generated prostanoid, has an essential role in growth and survival of colon cancer cell's. PGE2 exerts various effects in colon cancer cells including enhanced expansion, angiogenesis, survival, invasion, and migration. The signaling of PGE2 via the EP4 receptor has been shown to induce colon tumorigenesis. Moreover, the expression levels of the EP4 receptor significantly affect tumor growth and development. Overexpression of EP4 by various mechanisms increases survival and tumor vasculature in colon cancer cells. It seems that the pathway starting with COX2, continuing with PGE2, and ending with EP4 can promote the spread and growth of colon cancer. Therefore, targeting the COX-2/PGE2/EP4 axis can be considered as a worthy therapeutic approach to treat colon cancer. In this review, we have examined the role and different mechanisms that the EP4 receptor is involved in the development of colon cancer.
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Osawa K, Umemura M, Nakakaji R, Tanaka R, Islam RM, Nagasako A, Fujita T, Yokoyama U, Koizumi T, Mitsudo K, Ishikawa Y. Prostaglandin E 2 receptor EP4 regulates cell migration through Orai1. Cancer Sci 2019; 111:160-174. [PMID: 31755615 PMCID: PMC6942437 DOI: 10.1111/cas.14247] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 12/17/2022] Open
Abstract
The EP4 prostanoid receptors are one of four receptor subtypes for prostaglandin E2 (PGE2 ). Therefore, EP4 may play an important role in cancer progression. However, little information is available regarding their function per se, including migration and the cellular signaling pathway of EP4 in oral cancer. First, we found that mRNA and protein expression of EP4 was abundantly expressed in human-derived tongue squamous cell carcinoma cell lines HSC-3 and OSC-19. The EP4 agonist (ONO-AE1-437) significantly promoted cell migration in HSC-3 cells. In contrast, knockdown of EP4 reduced cell migration. Furthermore, we confirmed that knockdown of EP4 suppressed metastasis of oral cancer cells in the lungs of mice in vivo. Therefore, we focused on the mechanism of migration/metastasis in EP4 signaling. Interestingly, EP4 agonist significantly induced intracellular Ca2+ elevation not in only oral cancer cells but also in other cells, including normal cells. Furthermore, we found that EP4 activated PI3K and induced Ca2+ influx through Orai1 without activation of store depletion and stromal interaction molecule 1 (STIM1). Immunoprecipitation showed that EP4 formed complexes with Orai1 and TRPC1, but not with STIM. Moreover, the EP4 agonist ONO-AE1-437 phosphorylated ERK and activated MMP-2 and MMP-9. Knockdown of Orai1 negated EP4 agonist-induced ERK phosphorylation. Taken together, our data suggested that EP4 activated PI3K and then induced Ca2+ influx from the extracellular space through Orai1, resulting in ERK phosphorylation and promoting cell migration. Migration is regulated by EP4/PI3K/Orai1 signaling in oral cancer.
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Affiliation(s)
- Kohei Osawa
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.,Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masanari Umemura
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Rina Nakakaji
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.,Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryo Tanaka
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Rafikul Md Islam
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Akane Nagasako
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takayuki Fujita
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Utako Yokoyama
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.,Department of Physiology, Tokyo Medical University Graduate School of Medicine, Tokyo, Japan
| | - Toshiyuki Koizumi
- Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kenji Mitsudo
- Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yoshihiro Ishikawa
- Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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10
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Han IH, Kim JH, Jang KS, Ryu JS. Inflammatory mediators of prostate epithelial cells stimulated with Trichomonas vaginalis promote proliferative and invasive properties of prostate cancer cells. Prostate 2019; 79:1133-1146. [PMID: 31050003 DOI: 10.1002/pros.23826] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/29/2019] [Accepted: 04/17/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Trichomonas vaginalis (Tv) is the most common sexually transmitted parasite. It is detected in prostatic tissue of benign prostatic hyperplasia, prostatitis, and prostate cancer (PCa) and has been suggested to cause chronic prostatitis. Moreover, up to 20% of all cancers worldwide are associated with chronic inflammation. Here, we investigated whether inflammatory mediators produced by normal human prostate epithelial cells (RWPE-1) stimulated with Tv could promote growth and invasiveness of PCa cells. METHODS Conditioned medium of RWPE-1 cells was prepared by stimulating them with Tv (trichomonad-conditioned medium [TCM]) and without Tv (conditioned medium [CM]). Promotion of PCa cells (PC3, DU145, and LNCaP) was assessed by wound healing, proliferation, and invasion assays. RESULTS We observed that the production of interleukin (IL)-1β, IL-6, CCL2, CXCL8, prostaglandin-E2 (PGE2 ), and COX2 by RWPE-1 cells was increased by stimulating them with Tv. When PCa cells were incubated with TCM, their proliferation, invasion, and migration increased. Moreover, they showed increased epithelial-mesenchymal transition (EMT)-related markers by a reduction in epithelial markers and an increase in mesenchymal markers. In vivo, xenograft tumor tissues injected with TCM also showed increased expression of cyclin D1 and proliferating cell nuclear antigen, as well as induction of EMT. Receptors and signal molecules of PCa cells increased in response to exposure to TCM, and blocking receptors (CXCR1, CXCR2, C-C chemokine receptor 2, glycoprotein 130, EP2, and EP4) reduced the proliferation of PCa cells with decreased production of cytokines (CCL2, IL-6, and CXCL8) and PGE2 , and expression of NF-κB and Snail1. CONCLUSIONS Our results suggest that Tv infection may be one of the factors creating the supportive microenvironment to promote proliferation and invasiveness of PCa cells.
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Affiliation(s)
- Ik-Hwan Han
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul, Korea
| | - Jung-Hyun Kim
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul, Korea
| | - Ki-Seok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Jae-Sook Ryu
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul, Korea
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Karpisheh V, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Ghalamfarsa G, Sabz G, Yousefi M, Yousefi B, Jadidi-Niaragh F. Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat 2019; 144:106338. [PMID: 31100474 DOI: 10.1016/j.prostaglandins.2019.106338] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/30/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Although colon cancer is one of the most important triggers of cancer related mortality, a few therapeutic options exist for this disease, including combination chemotherapy, anti-EGFR and anti-angiogenic agents. However, none of these therapeutics are fully effective for complete remission, and this issue needs further investigations, particularly in the patients with advanced disease. It has been shown that colon carcinogenesis process is associated with upregulation of prostaglandin (PG) levels. Moreover, conversion of pre-malignant cells to malignant was also related with increased generation of PGs in susceptible subjects. Among the prostanoids, PGE2 is the most important produced member which generated in high levels by colon tumor cells. Generation of PGE2 by action of cyclooxygenase (COX)-2 can promote growth and development, resistance to apoptosis, proliferation, invasion and metastasis, angiogenesis and drug resistance in colon cancer. Increased levels of PGE2 and COX-2 in colon cancer is reported by various investigators which was associated with disease progression. It is suggested that there is a positive feedback loop between COX-2 and PGE2, in which function of COX-2 induces generation of PGE2, and upregulation of PGE2 increases the expression of COX-2 in colon cancer. Although an existence of this feedback loop is well-documented, its precise mechanism, signaling pathways, and the particular E-type prostanoid (EP) receptor mediating this feedback are elusive. Therefore, it seems that targeting COX-2/PGE2/EP receptors may be supposed as a potent therapeutic strategy for treatment of colon cancer. In this review, we try to clarify the role of PGE2 in cancer progression and its targeting for treatment of colon cancer.
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Affiliation(s)
- Vahid Karpisheh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Afshin Nikkhoo
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Afshin Namdar
- Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2E1 Canada
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Gholamabas Sabz
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Abstract
Eicosanoids are bioactive lipids that play crucial roles in various pathophysiological conditions, including inflammation and cancer. They include both the COX-derived prostaglandins and the LOX-derived leukotrienes. Furthermore, the epidermal growth factor receptor (EGFR) pathways family of receptor tyrosine kinases also are known to play a central role in the tumorigenesis. Various antitumor modalities have been approved cancer treatments that target therapeutically the COX-2 and EGFR pathways; these include selective COX-2 inhibitors and EGFR monoclonal antibodies. Research has shown that the COX-2 and epidermal growth factor receptor pathways actively interact with each other in order to orchestrate carcinogenesis. This has been used to justify a targeted combinatorial approach aimed at these two pathways. Although combined therapies have been found to have a greater antitumor effect than the administration of single agent, this does not exempt them from the possible fatal cardiac effects that are associated with COX-2 inhibition. In this review, we delineate the contribution of HB-EGF, an important EGFR ligand, to the cardiac dysfunction related to decreased shedding of HB-EGF after COX-2/PGE2 inhibition. A better understanding of the molecular mechanisms underlying these cardiac side effects will make possible more effective regimens that use the dual-targeting approach.
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Affiliation(s)
- Cheng-Chieh Yang
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
- School of Dentistry, National Yang-Ming University, Taipei, Taiwan
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuo-Wei Chang
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
- School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
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13
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Singh N, Bansal M, Pal S, Alam S, Jagdale P, Ayanur A, Ansari KM. COX-2/EP2-EP4/β-catenin signaling regulates patulin-induced intestinal cell proliferation and inflammation. Toxicol Appl Pharmacol 2018; 356:224-234. [DOI: 10.1016/j.taap.2018.08.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 07/31/2018] [Accepted: 08/16/2018] [Indexed: 12/29/2022]
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14
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Guillem-Llobat P, Dovizio M, Bruno A, Ricciotti E, Cufino V, Sacco A, Grande R, Alberti S, Arena V, Cirillo M, Patrono C, FitzGerald GA, Steinhilber D, Sgambato A, Patrignani P. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget 2018; 7:32462-77. [PMID: 27074574 PMCID: PMC5078026 DOI: 10.18632/oncotarget.8655] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 03/28/2016] [Indexed: 12/30/2022] Open
Abstract
We investigated whether platelets prime colon cancer cells for metastasis and whether pharmacological inhibition of platelet function may prevent it. Coculturing HT29 human colon carcinoma cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of E-cadherin and upregulation of Twist1, enhanced cell mobility and a proaggregatory action on platelets. These changes were prevented by different antiplatelet agents, aspirin[an inhibitor of cyclooxygenase(COX)-1], DG-041[an antagonist of prostaglandin(PG)E2 EP3 receptor] and ticagrelor (a P2Y12 receptor antagonist). The injection of HT29 cells, exposed to platelets in vitro, into the tail vein of humanized immunodeficient mice led to higher incidence of lung metastasis compared to the injection of untreated HT29 cells. This effect was associated with enhanced systemic biosynthesis of thromboxane(TX)A2 and PGE2in vivo. Platelet COX-1 inhibition by aspirin administration to mice prevented the increased rate of metastasis as well as the enhanced production of TXA2 and PGE2 induced by the in vitro priming of HT29 cells by platelets. In conclusion, targeting platelet COX-1 with low-dose aspirin exerts an antimetastatic action by averting the stem cell mimicry of cancer cells associated with enhanced proaggregatory effects induced by platelet-tumor cell interactions. These effects may be shared by other antiplatelet drugs.
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Affiliation(s)
- Paloma Guillem-Llobat
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
| | - Melania Dovizio
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
| | - Annalisa Bruno
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
| | - Emanuela Ricciotti
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA
| | - Valerio Cufino
- Institute of General Pathology, Catholic University School of Medicine, Rome, Italy
| | - Angela Sacco
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
| | - Rosalia Grande
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
| | - Sara Alberti
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
| | - Vincenzo Arena
- Institute of Pathologic Anatomy, Catholic University, School of Medicine, Rome, Italy
| | - Mariangela Cirillo
- Institute of Pathologic Anatomy, Catholic University, School of Medicine, Rome, Italy
| | - Carlo Patrono
- Institute of Pharmacology, Catholic University, School of Medicine, Rome, Italy
| | - Garret A FitzGerald
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany
| | - Alessandro Sgambato
- Institute of General Pathology, Catholic University School of Medicine, Rome, Italy
| | - Paola Patrignani
- Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy
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15
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Synthesis and evaluation of 18 F-labeled CJ-042794 for imaging prostanoid EP4 receptor expression in cancer with positron emission tomography. Bioorg Med Chem Lett 2017; 27:2094-2098. [DOI: 10.1016/j.bmcl.2017.03.078] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 03/24/2017] [Accepted: 03/25/2017] [Indexed: 12/25/2022]
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16
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Moreno JJ. Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis. Eur J Pharmacol 2016; 796:7-19. [PMID: 27940058 DOI: 10.1016/j.ejphar.2016.12.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/30/2016] [Accepted: 12/05/2016] [Indexed: 12/25/2022]
Abstract
The importance of cyclooxygenase and lipoxygenase pathways and the consequent eicosanoid synthesis in the physiology and pathophysiology of the intestinal epithelium is currently being established. Each eicosanoid (prostanoid, leukotriene, hydroxyeicosatetraenoic acid) preferentially recognizes one or more receptors coupled to one or more signal-transduction processes. This overview focuses on the role of eicosanoid receptors in the maintenance of intestinal epithelium physiology through the control of proliferation/differentiation/apoptosis processes. Furthermore, it is reported that the role of these receptors on the regulation of the barrier function of the intestinal epithelium have arisen through the regulation of absorption/secretion processes, tight-junction state and the control of the intestinal immune response. Also, this review considers the implication of AA cascade in the disruption of epithelial homeostasis during inflammatory bowel diseases and colorectal cancer as well as the therapeutic values and potential of the eicosanoid receptors as novel targets for the treatments of the pathologies above mentioned.
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Affiliation(s)
- Juan J Moreno
- Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, Avda. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
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17
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Alba-Castellón L, Olivera-Salguero R, Mestre-Farrera A, Peña R, Herrera M, Bonilla F, Casal JI, Baulida J, Peña C, García de Herreros A. Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis. Cancer Res 2016; 76:6205-6217. [PMID: 27503928 DOI: 10.1158/0008-5472.can-16-0176] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 06/24/2016] [Indexed: 11/16/2022]
Abstract
Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here an EMT-independent action of Snail1 on tumor invasion, as it is required for the activation of cancer-associated fibroblasts (CAF). Snail1 expression in fibroblasts requires signals derived from tumor cells, such as TGFβ; reciprocally, in fibroblasts, Snail1 organizes a complex program that stimulates invasion of epithelial cells independent of the expression of Snail1 in these cells. Epithelial cell invasion is stimulated by the secretion by fibroblast of diffusible signaling molecules, such as prostaglandin E2 The capability of human or murine CAFs to promote tumor invasion is dependent on Snail1 expression. Inducible Snail1 depletion in mice decreases the invasion of breast tumors; moreover, epithelial tumor cells coxenografted with Snail1-depleted fibroblasts originated tumors with lower invasion than those transplanted with control fibroblasts. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to EMT, but it is also dependent on its activity in stromal fibroblasts, where it orchestrates the cross-talk with epithelial tumor cells. Cancer Res; 76(21); 6205-17. ©2016 AACR.
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Affiliation(s)
- Lorena Alba-Castellón
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Rubén Olivera-Salguero
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Aida Mestre-Farrera
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Raúl Peña
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Mercedes Herrera
- Servicio de Oncología Médica, Hospital Puerta de Hierro, Majadahonda, Spain
| | | | | | - Josep Baulida
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Cristina Peña
- Servicio de Oncología Médica, Hospital Puerta de Hierro, Majadahonda, Spain
| | - Antonio García de Herreros
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain. .,Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
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18
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Kim SH, Park YY, Cho SN, Margalit O, Wang D, DuBois RN. Krüppel-Like Factor 12 Promotes Colorectal Cancer Growth through Early Growth Response Protein 1. PLoS One 2016; 11:e0159899. [PMID: 27442508 PMCID: PMC4956169 DOI: 10.1371/journal.pone.0159899] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 07/11/2016] [Indexed: 01/05/2023] Open
Abstract
Krüppel-like factor 12 (KLF12) is a transcription factor that plays a role in normal kidney development and repression of decidualization. KLF12 is frequently elevated in esophageal adenocarcinoma and has been reported to promote gastric cancer progression. Here, we examined the role of KLF12 in colorectal cancer (CRC). Indeed, KLF12 promotes tumor growth by directly activating early growth response protein 1 (EGR1). The levels of KLF12 and EGR1 correlate synergistically with a poor prognosis. These results indicate that KLF12 likely plays an important role in CRC and could serve as a potential prognostic marker and therapeutic target.
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Affiliation(s)
- Sun-Hee Kim
- Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Yun-Yong Park
- ASAN Institute for Life Sciences, ASAN Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul 138–736, Korea
| | - Sung-Nam Cho
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ofer Margalit
- Biodesign Institute of Arizona State University, Tempe, Arizona, United States of America
| | - Dingzhi Wang
- Biodesign Institute of Arizona State University, Tempe, Arizona, United States of America
| | - Raymond N. DuBois
- Biodesign Institute of Arizona State University, Tempe, Arizona, United States of America
- Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona, United States of America
- Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona, United States of America
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America
- * E-mail:
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19
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Shishikura K, Horiuchi T, Sakata N, Trinh DA, Shirakawa R, Kimura T, Asada Y, Horiuchi H. Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. Br J Pharmacol 2015; 173:319-31. [PMID: 26505736 DOI: 10.1111/bph.13373] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 10/05/2015] [Accepted: 10/12/2015] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND AND PURPOSE Upon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs), which contain unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defence, although the role of PGE2 , a bioactive substance generated in inflammatory tissues, in the formation of NETs remains unclear. EXPERIMENTAL APPROACH The effects of PGE2 , agonists and antagonists of its receptors, and modulators of the cAMP-PKA pathway on the formation of NETs were examined in vitro in isolated neutrophils and in vivo in a newly established mouse model. KEY RESULTS PGE2 inhibited PMA-induced NET formation in vitro through EP2 and EP4 Gαs-coupled receptors. Incubation with a cell-permeable cAMP analogue, dibutyryl cAMP, or various inhibitors of a cAMP-degrading enzyme, PDE, also suppressed NET formation. In the assay established here, where an agarose gel was s.c. implanted in mice and NET formation was detected on the surface of the gel, the extent of the NET formed was inhibited in agarose gels containing rolipram, a PDE4 inhibitor, and butaprost, an EP2 receptor agonist. CONCLUSIONS AND IMPLICATIONS PGE2 inhibits NET formation through the production of cAMP. These findings will contribute to the development of novel treatments for NETosis-related diseases.
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Affiliation(s)
- Kyosuke Shishikura
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Takahiro Horiuchi
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Natsumi Sakata
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Duc-Anh Trinh
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.,The Department of Oral Cancer Therapeutics, Graduate School of Dentistry, Tohoku University, Sendai, Japan
| | - Ryutaro Shirakawa
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Tomohiro Kimura
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Yujiro Asada
- The Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Hisanori Horiuchi
- The Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.,The Department of Oral Cancer Therapeutics, Graduate School of Dentistry, Tohoku University, Sendai, Japan
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20
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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21
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Chang J, Vacher J, Yao B, Fan X, Zhang B, Harris RC, Zhang MZ. Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis. Oncotarget 2015; 6:33500-11. [PMID: 26378024 PMCID: PMC4741781 DOI: 10.18632/oncotarget.5589] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 08/23/2015] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. Although the factors underlying CRC development and progression are multifactorial, there is an important role for tumor-host interactions, especially interactions with myeloid cells. There is also increasing evidence that cyclooxygenase-derived prostaglandins are important mediators of CRC development and growth. Although prevention trials with either nonselective NSAIDs or COX-2 selective agents have shown promise, the gastrointestinal or cardiovascular side effects of these agents have limited their implementation. The predominant prostaglandin involved in CRC pathogenesis is PGE2. Since myeloid cells express high levels of the PGE2 receptor subtype, EP4, we selectively ablated EP4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, ApcMin/+ mice. ApcMin/+mice with selective myeloid cell deletion of EP4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE2-mediated EP4 signaling in myeloid cells promotes tumorigenesis, suggesting EP4 as a potentially attractive target for CRC chemoprevention or treatment.
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Affiliation(s)
- Jian Chang
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
- Hepatobiliary Surgery Department, Wuhan No.1 Hospital, Wuhan, China
| | - Jean Vacher
- Départment of Médecine, Clinical Research Institute of Montreal, Université de Montréal, Montreal, Quebec, Canada
| | - Bing Yao
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Xiaofeng Fan
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Raymond C. Harris
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Ming-Zhi Zhang
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
- Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
- Jiangsu Center for The Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China
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22
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Prostanoids regulate angiogenesis acting primarily on IP and EP4 receptors. Microvasc Res 2015; 101:127-34. [DOI: 10.1016/j.mvr.2015.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 07/02/2015] [Accepted: 07/15/2015] [Indexed: 02/02/2023]
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23
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Cabral M, Martín-Venegas R, Moreno JJ. Leukotriene D4-induced Caco-2 cell proliferation is mediated by prostaglandin E2 synthesis. Physiol Rep 2015. [PMID: 26216432 PMCID: PMC4552517 DOI: 10.14814/phy2.12417] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Leukotriene D4 (LTD4) is a pro-inflammatory mediator formed from arachidonic acid through the action of 5-lipoxygenase (5-LOX). Its biological effects are mediated by at least two G-coupled plasmatic cysteinyl LT receptors (CysLT1-2R). It has been reported an upregulation of the 5-LOX pathway in tumor tissue unlike in normal colon mucosa. Colon tumors generally have an increased expression of CysLT1R and colon cancer patients with high expression levels of CysLT1R have poor prognosis. We previously observed that the cyclooxygenase pathway is involved in the control of intestinal epithelial cancer cell growth through PGE2 production. The aim of this study was therefore to assess the effect of LTD4 binding with CysLT1R on Caco-2 cell growth. We note a number of key findings from this research. We observed that at a concentration similar to that found under inflammatory conditions, LTD4 was able to induce Caco-2 cell proliferation and DNA synthesis. Moreover, with the use of a specific receptor antagonist this study has demonstrated that the effect of LTD4 is a result of its interaction with CystLT1R. We also note the possible participation of the PLC-IP3-Ca2+/DAG-PKC signaling pathways in cytosolic PLA2 and [3H]AA release induced by LTD4-CystLT1R interaction. Finally, we found that the resulting activation of the AA cascade and the production of PGE2 eicosanoid could be related to the activation of cell signaling pathways such as ERK and CREB. These findings will help facilitate our understanding of how inflammatory mediators can affect the survival and dissemination of intestinal carcinoma cells.
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Affiliation(s)
- Marisol Cabral
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Raquel Martín-Venegas
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Juan J Moreno
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
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Li N, Zhang L, An Y, Zhang L, Song Y, Wang Y, Tang H. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice. J Proteome Res 2015; 14:1566-73. [PMID: 25669961 DOI: 10.1021/pr501236y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4.
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Affiliation(s)
- Ning Li
- Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences , Wuhan, 430071, P. R. China
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Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFβ-induced mice mesangial cell damage. Biosci Rep 2014; 34:e00159. [PMID: 25327961 PMCID: PMC4266927 DOI: 10.1042/bsr20140130] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFβ1 (transforming growth factor-β1); however, the molecular mechanisms for this remain unknown. The present study examined the role of the EP2 signalling pathway in TGFβ1-induced MCs proliferation, ECM (extracellular matrix) accumulation and expression of PGES (prostaglandin E2 synthase). We generated primary mice MCs. Results showed MCs proliferation promoted by TGFβ1 were increased; however, the production of cAMP and PGE2 (prostaglandin E2) was decreased. EP2 deficiency in these MCs augmented FN (fibronectin), Col I (collagen type I), COX2 (cyclooxygenase-2), mPGES-1 (membrane-associated prostaglandin E1), CTGF (connective tissue growth factor) and CyclinD1 expression stimulated by TGFβ1. Silencing of EP2 also strengthened TGFβ1-induced p38MAPK (mitogen-activated protein kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2) and CREB1 (cAMP responsive element-binding protein 1) phosphorylation. In contrast, Adenovirus-mediated EP2 overexpression reversed the effects of EP2-siRNA (small interfering RNA). Collectively, the investigation indicates that EP2 may block p38MAPK, ERK1/2 and CREB1 phosphorylation via activation of cAMP production and stimulation of PGE2 through EP2 receptors which prevent TGFβ1-induced MCs damage. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the damage induced by TGFβ1.
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EP2 and EP4 receptors mediate PGE2 induced relaxation in murine colonic circular muscle: Pharmacological characterization. Pharmacol Res 2014; 90:76-86. [DOI: 10.1016/j.phrs.2014.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 10/07/2014] [Accepted: 10/13/2014] [Indexed: 01/27/2023]
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Ma X, Holt D, Kundu N, Reader J, Goloubeva O, Take Y, Fulton AM. A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE 2-mediated immunosuppression and inhibits breast cancer metastasis. Oncoimmunology 2014; 2:e22647. [PMID: 23482441 PMCID: PMC3583931 DOI: 10.4161/onci.22647] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cyclooxygenase-2 is frequently upregulated in epithelial tumors and contributes to poor outcomes in multiple malignancies. The COX-2 product prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four G protein-coupled receptors (EP1-4). Using a novel small molecule EP4 antagonist (RQ-15986) and a syngeneic murine model of metastatic breast cancer, we determined the effect of EP4 blockade on innate immunity and tumor biology. Natural killer (NK)-cell functions are markedly depressed in mice bearing murine mammary tumor 66.1 or 410.4 cells owing to the actions of PGE2 on NK cell EP4 receptors. The EP4 agonist PGE1-OH inhibits NK functions in vitro, and this negative regulation is blocked by RQ-15986. Likewise, the treatment of tumor-bearing mice with RQ-15986 completely protected NK cells from the immunosuppressive effects of the tumor microenvironment in vivo. RQ-15986 also has direct effects on EP4 expressed by tumor cells, inhibiting the PGE2-mediated activation of adenylate cyclase and blocking PGE2-induced tumor cell migration. The pretreatment of tumor cells with a non-cytotoxic concentration of RQ-15986 inhibited lung colonization, a beneficial effect that was lost in mice depleted of NK cells. The oral administration of RQ-15986 inhibited the growth of tumor cells implanted into mammary glands and their spontaneous metastatic colonization to the lungs, resulting in improved survival. Our findings reveal that EP4 antagonism prevents tumor-mediated NK-cell immunosuppression and demonstrates the anti-metastatic activity of a novel EP4 antagonist. These observations support the investigation of EP4 antagonists in clinical trials.
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Affiliation(s)
- Xinrong Ma
- University of Maryland Greenebaum Cancer Center; Baltimore, MD USA
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28
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Cabral M, Martín-Venegas R, Moreno JJ. Differential cell growth/apoptosis behavior of 13-hydroxyoctadecadienoic acid enantiomers in a colorectal cancer cell line. Am J Physiol Gastrointest Liver Physiol 2014; 307:G664-71. [PMID: 25035111 DOI: 10.1152/ajpgi.00064.2014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cyclooxygenases (COXs) and lipoxygenases (LOXs) are important enzymes that metabolize arachidonic and linoleic acids. Various metabolites generated by the arachidonic acid cascade regulate cell proliferation, apoptosis, differentiation, and senescence. Hydroxyoctadecadienoic acids (HODEs) are synthesized from linoleic acid, giving two enantiomeric forms for each metabolite. The aim was to investigate the effect of 13-HODE enantiomers on nondifferentiated Caco-2 cell growth/apoptosis. Our results indicate that 13(S)-HODE decreases cell growth and DNA synthesis of nondifferentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS). Moreover, 13(S)-HODE showed an apoptotic effect that was reduced in the presence of a specific peroxisome proliferator-activated receptor-γ (PPARγ) antagonist. In addition, we observed that 13(S)-HODE but not 13(R)-HODE is a ligand to PPARγ, confirming the implication of this nuclear receptor in 13(S)-HODE actions. In contrast, 13(R)-HODE increases cell growth and DNA synthesis in the absence of FBS. 13(R)-HODE interaction with BLT receptors activates ERK and CREB signaling pathways, as well as PGE2 synthesis. These results suggest that the proliferative effect of 13(R)-HODE could be due, at least in part, to COX pathway activation. Thus both enantiomers use different receptors and have contrary effects. We also found these differential effects of 9-HODE enantiomers on cell growth/apoptosis. Therefore, the balance between (R)-HODEs and (S)-HODEs in the intestinal epithelium could be important to its cell growth/apoptosis homeostasis.
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Affiliation(s)
- Marisol Cabral
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Raquel Martín-Venegas
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Juan José Moreno
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
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Chae IG, Kim DH, Kundu J, Jeong CH, Kundu JK, Chun KS. Generation of ROS by CAY10598 leads to inactivation of STAT3 signaling and induction of apoptosis in human colon cancer HCT116 cells. Free Radic Res 2014; 48:1311-21. [PMID: 25096910 DOI: 10.3109/10715762.2014.951838] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Prostaglandin E2 (PGE2) has been reported to play critical roles in cell fate decision by interacting with four types of prostanoid receptors such as EP1, EP2, EP3 and EP4. The present study was aimed at investigating the effect of the EP4-specific agonist CAY10598 in human colon cancer HCT116 cells. Our study revealed that treatment with CAY10598 significantly reduced the cell viability and induced apoptosis in HCT116 cells, as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, -7, and -3, and PARP, and the inhibition of Bcl-2, Bcl-xL and survivin expression. Moreover, treatment with CAY10598 diminished the phosphorylation of JAK2, leading to the attenuation of STAT3 activation in HCT116 cells. CAY10598-induced apoptosis in cells which were transiently transfected with EP4 siRNA or treated with an EP4 antagonist prior to incubation with the compound remained unaffected, suggesting an EP4-independent mechanism of apoptosis induction by CAY10598. We found that treatment with CAY10598 generated reactive oxygen species (ROS) and pretreatment of cells with N-acetyl cysteine rescued cells from apoptosis by abrogating the inhibitory effect of CAY10598 on the activation of JAK2/STAT3 signaling. In conclusion, CAY10598 induced apoptosis in HCT116 cells in an EP4-independent manner, but through the generation of ROS and inactivation of JAK2/STAT3 signaling.
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Affiliation(s)
- I G Chae
- College of Pharmacy, Keimyung University , Daegu , South Korea
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Sales KJ, Adefuye A, Nicholson L, Katz AA. CCR5 expression is elevated in cervical cancer cells and is up-regulated by seminal plasma. Mol Hum Reprod 2014; 20:1144-57. [PMID: 25103627 DOI: 10.1093/molehr/gau063] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The interplay between inflammation, cervical cancer and HIV acquisition in women is poorly understood. We have previously shown that seminal plasma (SP) can promote cervical tumour cell growth in vitro and in vivo via the activation of potent inflammatory pathways. In this study, we investigated whether SP could regulate expression of chemokine receptors with known roles in HIV infection, in the cervix and in cervical cancer. The expression of CD4 and CCR5 was investigated by RT-PCR analysis and immunohistochemistry. CD4 and CCR5 expression was elevated in cervical cancer tissue compared with normal cervix. Ex vivo studies conducted on cervical tissues and HeLa cells showed that SP significantly increases the expression of CD4 and CCR5 transcripts. Furthermore, it was found that SP also up-regulates CCR5 protein in HeLa cells. The regulation of CCR5 expression was investigated following treatment of HeLa cells with SP in the presence/absence of chemical inhibitors of intracellular signalling, EP2 and EP4 antagonists, prostaglandin (PG) E2 and a cyclooxygenase (COX)-1 doxycycline-inducible expression system. These experiments demonstrated that the regulation of CCR5 expression by SP occurs via the epidermal growth factor receptor (EGFR)-COX-1-PGE2 pathway. This study provides a link between activation of inflammatory pathways and regulation of HIV receptor expression in cervical cancer cells.
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Affiliation(s)
- Kurt J Sales
- MRC/UCT Receptor Biology Research Unit, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Anthonio Adefuye
- MRC/UCT Receptor Biology Research Unit, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Lauren Nicholson
- MRC/UCT Receptor Biology Research Unit, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Arieh A Katz
- MRC/UCT Receptor Biology Research Unit, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
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Snyder NW, Revello SD, Liu X, Zhang S, Blair IA. Cellular uptake and antiproliferative effects of 11-oxo-eicosatetraenoic acid. J Lipid Res 2013; 54:3070-7. [PMID: 23945567 PMCID: PMC3793611 DOI: 10.1194/jlr.m040741] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cyclooxygenases (COX) metabolize arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETE), which can then be oxidized by dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), to oxo-eicosatetraenoic acids (ETE). We have previously established that 11-oxo-eicosatetraenoic acid (oxo-ETE) and 15-oxo-ETE are COX-2/15-PGDH-derived metabolites. Stable isotope dilution (SID) chiral liquid chromatography coupled with electron capture atmospheric pressure chemical ionization (ECAPCI) single reaction monitoring (SRM) MS has been used to quantify uptake of 11-oxo-ETE and 15-oxo-ETE in both LoVo cells and human umbilical vein endothelial cells (HUVEC). Intracellular 11-oxo- and 15-oxo-ETE concentrations reached maximum levels within 1 h and declined rapidly, with significant quantitative differences in uptake between the LoVo cells and the HUVECs. Maximal intracellular concentrations of 11-oxo-ETE were 0.02 ng/4 × 105 cells in the LoVo cells and 0.58 ng/4 × 105 cells in the HUVECs. Conversely, maximal levels of 15-oxo-ETE were 0.21 ng/4 × 105 in the LoVo cells and 0.01 ng/4 × 105 in the HUVECs. The methyl esters of both 11-oxo- and 15-oxo-ETE increased the intracellular concentrations of the corresponding free oxo-ETEs by 3- to 8-fold. 11-oxo-ETE, 15-oxo-ETE, and their methyl esters inhibited proliferation in both HUVECs and LoVo cells at concentrations of 2–10 μM, with 11-oxo-ETE methyl ester being the most potent inhibitor. Cotreatment with probenecid, an inhibitor of multiple drug resistance transporters (MRP)1 and 4, increased the antiproliferative effect of 11-oxo-ETE methyl ester in LoVo cells and increased the intracellular concentration of 11-oxo-ETE from 0.05 ng/4 × 105 cells to 0.18 ng/4 × 105 cells. Therefore, this study has established that the COX-2/15-PGDH-derived eicosanoids 11-oxo- and 15-oxo-ETE enter target cells, that they inhibit cellular proliferation, and that their inhibitory effects are modulated by MRP exporters.
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Affiliation(s)
- Nathaniel W Snyder
- Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA
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Yokoyama U, Iwatsubo K, Umemura M, Fujita T, Ishikawa Y. The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev 2013; 65:1010-52. [PMID: 23776144 DOI: 10.1124/pr.112.007195] [Citation(s) in RCA: 204] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The EP4 prostanoid receptor is one of four receptor subtypes for prostaglandin E2. It belongs to the family of G protein-coupled receptors. It was originally identified, similar to the EP2 receptor as a G(s)α-coupled, adenylyl cyclase-stimulating receptor. EP4 signaling plays a variety of roles through cAMP effectors, i.e., protein kinase A and exchange protein activated by cAMP. However, emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that EP4, unlike EP2, can also be coupled to G(i)α, phosphatidylinositol 3-kinase, β-arrestin, or β-catenin. These signaling pathways constitute unique roles for the EP4 receptor. EP4 is widely distributed in the body and thus plays various physiologic and pathophysiologic roles. In particular, EP4 signaling is closely related to carcinogenesis, cardiac hypertrophy, vasodilation, vascular remodeling, bone remodeling, gastrointestinal homeostasis, renal function, and female reproductive function. In addition to the classic anti-inflammatory action of EP4 on mononuclear cells and T cells, recent evidence has shown that EP4 signaling contributes to proinflammatory action as well. The aim of this review is to present current findings on the biologic functions of the EP4 receptor. In particular, we will discuss its diversity from the standpoint of EP4-mediated signaling.
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Affiliation(s)
- Utako Yokoyama
- Cardiovascular Research Institute, Yokohama City University, Yokohama, Kanagawa, Japan
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Cabral M, Martín-Venegas R, Moreno JJ. Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth. Int J Biochem Cell Biol 2013; 45:1620-8. [PMID: 23685077 DOI: 10.1016/j.biocel.2013.05.009] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 04/26/2013] [Accepted: 05/09/2013] [Indexed: 11/29/2022]
Abstract
Increasingly evidence indicates that enzymes, receptors and metabolites of the arachidonic acid (AA) cascade play a role in intestinal epithelial cell proliferation and colorectal tumorigenesis. However, the information available does not provide a complete picture and contains a number of discrepancies. For this reason it might be appropriate a thorough study into the impacts of the AA cascade on intestinal epithelial cell growth. Our data show that non-differentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS) synthesize appreciable amounts of prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and 5-, 12 and 15-hydroxyeicosatetraenoic acid (HETE) but not LTD4, 20-HETE and epoxyeicosatrienoic acids. We also found that inhibitors of PGE2, LTB4 and 5-, 12-, 15-HETE synthesis as well as receptor antagonists of PGE2 and LTB4 blocked Caco-2 cell growth and DNA synthesis induced by 10% FBS without cytotoxic or apoptotic activity. Interestingly, PGE2, LTB4 and 5-, 12- and 15-HETE at concentrations reached in 10% FBS Caco-2 cultures (1-10nM) were able to induce Caco-2 cell growth and DNA synthesis. This was due to the interaction of PGE2 with EP1 and EP4 receptors and LTB4 and HETEs with BLT1 and BLT2 receptors. Moreover, we provide evidence that PGE2 stimulates several cell signaling pathways such as ERK, P38α, CREB and GSKβ/β-catenin involved in the regulation of Caco-2 growth. Finally, we provide evidence that the mitogenic effects of LTB4 and HETEs can be dependent, at least in part, on PGE2 synthesis.
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Affiliation(s)
- Marisol Cabral
- Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
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Multilevel pharmacological manipulation of adenosine-prostaglandin E₂/cAMP nexus in the tumor microenvironment: a 'two hit' therapeutic opportunity. Pharmacol Res 2013; 73:8-19. [PMID: 23619528 DOI: 10.1016/j.phrs.2013.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 04/14/2013] [Indexed: 02/06/2023]
Abstract
Novel trends in cancer treatment research are focused on targeting the tumor microenvironment, thereby developing chemo-immunotherapeutic strategies which not only directly kill tumor cells, but also trigger the anti-tumor immune effector responses. Ectonucleotidases (CD39 and CD73)-generated extracellular adenosine and cyclooxygenase-2 (COX2)-derived prostaglandin E₂ (PGE₂) are amongst the tumor microenvironmental factors that have emerged as attractive targets in this regard. Both comprise a pivotal axis in tumor progression and immune escape via autocrine and paracrine activation of a common intracellular signaling pathway, the cAMP-protein kinase A (PKA) pathway, in cancer and immune cells. In this review, we venture a potential and realistic strategy that this adenosine-PGE₂/cAMP nexus is targetable at different levels, thereby pointing out a 'two hit' chemo-immunotherapeutic proposition: direct killing of tumor cells on one hand, and the rescuing of endogenous anti-tumor immune response on the other. The reviewed experimental, preclinical and clinical data provide the proof of concept that 'two hit' multilevel pharmacological manipulation of adenosine-E₂/cAMP nexus is achievable within the tumor microenvironment.
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Liu Y, Rajagopal M, Lee K, Battini L, Flores D, Gusella GL, Pao AC, Rohatgi R. Prostaglandin E(2) mediates proliferation and chloride secretion in ADPKD cystic renal epithelia. Am J Physiol Renal Physiol 2012; 303:F1425-34. [PMID: 22933297 DOI: 10.1152/ajprenal.00010.2012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Prostaglandin E(2) (PGE(2)) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE(2) induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE(2) induces proliferation and chloride (Cl(-)) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl(-) secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE(2) in cell proliferation. Exogenous administration of PGE(2) increased proliferation of PC-1-deficient cells by 38.8 ± 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 ± 1.9% (P < 0.05). Next, we tested whether PGE(2)-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream β-catenin activation. PGE(2) and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active β-catenin in PC-1-deficient cells, suggesting a mechanism for PGE(2)-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE(2)-dependent Cl(-) secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I(sc)). Addition of PGE(2) induced a fivefold higher increase in I(sc) in PC-1-deficient cells compared with PC-1-replete cells. This PGE(2)-induced increase in I(sc) in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE(2) activates CFTR and calcium-activated Cl(-) channels. In conclusion, PGE(2) activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE(2) inhibition and EP4 receptor antagonism.
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Affiliation(s)
- Yu Liu
- Department of Medicine, The Mount Sinai School of Medicine, New York, NY 10029, USA
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Ganesh K, Das A, Dickerson R, Khanna S, Parinandi NL, Gordillo GM, Sen CK, Roy S. Prostaglandin E₂ induces oncostatin M expression in human chronic wound macrophages through Axl receptor tyrosine kinase pathway. THE JOURNAL OF IMMUNOLOGY 2012; 189:2563-73. [PMID: 22844123 DOI: 10.4049/jimmunol.1102762] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Monocytes and macrophages (m) are plastic cells whose functions are governed by microenvironmental cues. Wound fluid bathing the wound tissue reflects the wound microenvironment. Current literature on wound inflammation is primarily based on the study of blood monocyte-derived macrophages, cells that have never been exposed to the wound microenvironment. We sought to compare pair-matched monocyte-derived macrophages with m isolated from chronic wounds of patients. Oncostatin M (OSM) was differentially overexpressed in pair-matched wound m. Both PGE₂ and its metabolite 13,14-dihydro-15-keto-PGE₂ (PGE-M) were abundant in wound fluid and induced OSM in wound-site m. Consistently, induction of OSM mRNA was observed in m isolated from PGE₂-enriched polyvinyl alcohol sponges implanted in murine wounds. Treatment of human THP-1 cell-derived m with PGE₂ or PGE-M caused dose-dependent induction of OSM. Characterization of the signal transduction pathways demonstrated the involvement of EP4 receptor and cAMP signaling. In human m, PGE₂ phosphorylated Axl, a receptor tyrosine kinase (RTK). Axl phosphorylation was also induced by a cAMP analogue demonstrating interplay between the cAMP and RTK pathways. PGE₂-dependent Axl phosphorylation led to AP-1 transactivation, which is directly implicated in inducible expression of OSM. Treatment of human m or mice excisional wounds with recombinant OSM resulted in an anti-inflammatory response as manifested by attenuated expression of endotoxin-induced TNF-α and IL-1β. OSM treatment also improved wound closure during the early inflammatory phase of healing. In summary, this work recognizes PGE₂ in the wound fluid as a potent inducer of m OSM, a cytokine with an anti-inflammatory role in cutaneous wound healing.
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Affiliation(s)
- Kasturi Ganesh
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Chandramouli A, Onyeagucha BC, Mercado-Pimentel ME, Stankova L, Shahin NA, LaFleur BJ, Heimark RL, Bhattacharyya AK, Nelson MA. MicroRNA-101 (miR-101) post-transcriptionally regulates the expression of EP4 receptor in colon cancers. Cancer Biol Ther 2012; 13:175-83. [PMID: 22353936 DOI: 10.4161/cbt.13.3.18874] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
PURPOSE Expression of the PGE2 receptor, EP4, is up-regulated during colorectal carcinogenesis. However the mechanism leading to deregulation of the EP4 receptor is not known. The present study was conducted to investigate the regulation of EP4 receptor by miRNAs. EXPERIMENTAL DESIGN We analyzed 26 colon cancers (i.e. 15 adenocarcinomas and 9 adenomas) and 16 normal colon specimens for EP4 receptor expression by immunohistochemistry. A bioinformatics approached identified putative microRNA binding sites with the 3'-UTR of the EP4 receptor. Both colon cancer cell lines and tumor specimens were analyzed for miR-101 and EP4 expression by qRT-PCR and Western analysis respectively and simultaneously in situ hybridizations was used to confirm our results. In vitro and in vivo assays were used to confirm our clinical findings. RESULTS We observed an inverse correlation between the levels of miR-101 and EP4 receptor protein. Transfection of LS174T cells with miR-101 significantly suppressed a luciferase reporter containing the EP4 receptor-3'-UTR. In contrast, a mutant EP4 receptor-3'-UTR construct was unaffected. Ectopic expression of miR-101 markedly reduced cell proliferation and motility. Co-transfection of EP4 receptor could rescue colon cancer cells from the tumor suppressive effects of miR-101. Moreover, the pharmacologic inhibition of EP4 receptor signaling or silencing of EP4 receptor phenocopied the effect of miR-101. This is the first study to show that the EP4 receptor is negatively regulated by miR-101. CONCLUSIONS These data provide new insights in the modulation of EP-4 receptor expression at the post-transcriptional level by miR-101 and suggests therapeutic strategies against miR-101 targets may be warranted.
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Kundu JK, Surh YJ. Emerging avenues linking inflammation and cancer. Free Radic Biol Med 2012; 52:2013-37. [PMID: 22391222 DOI: 10.1016/j.freeradbiomed.2012.02.035] [Citation(s) in RCA: 183] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 02/14/2012] [Accepted: 02/16/2012] [Indexed: 12/12/2022]
Abstract
The role of inflammation in carcinogenesis has been extensively investigated and well documented. Many biochemical processes that are altered during chronic inflammation have been implicated in tumorigenesis. These include shifting cellular redox balance toward oxidative stress; induction of genomic instability; increased DNA damage; stimulation of cell proliferation, metastasis, and angiogenesis; deregulation of cellular epigenetic control of gene expression; and inappropriate epithelial-to-mesenchymal transition. A wide array of proinflammatory cytokines, prostaglandins, nitric oxide, and matricellular proteins are closely involved in premalignant and malignant conversion of cells in a background of chronic inflammation. Inappropriate transcription of genes encoding inflammatory mediators, survival factors, and angiogenic and metastatic proteins is the key molecular event in linking inflammation and cancer. Aberrant cell signaling pathways comprising various kinases and their downstream transcription factors have been identified as the major contributors in abnormal gene expression associated with inflammation-driven carcinogenesis. The posttranscriptional regulation of gene expression by microRNAs also provides the molecular basis for linking inflammation to cancer. This review highlights the multifaceted role of inflammation in carcinogenesis in the context of altered cellular redox signaling.
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Abstract
Cancer initiation and progression are multistep events that require cell proliferation, migration, extravasation to the blood or lymphatic vessels, arrest to the metastatic site, and ultimately secondary growth. Tumor cell functions at both primary or secondary sites are controlled by many different factors, including growth factors and their receptors, chemokines, nuclear receptors, cell-cell interactions, cell-matrix interactions, as well as oxygenated metabolites of arachidonic acid. The observation that cyclooxygenases and lipoxygenases and their arachidonic acid-derived eicosanoid products (prostanoids and HETEs) are expressed and produced by tumor cells, together with the finding that these enzymes can regulate cell growth, survival, migration, and invasion, has prompted investigators to analyze the roles of these enzymes in cancer progression. In this review, we focus on the contribution of cyclooxygenase- and lipoxygenase-derived eicosanoids to tumor cell function in vitro and in vivo and discuss hope and tribulations of targeting these enzymes for cancer prevention and treatment.
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Affiliation(s)
- Claus Schneider
- Department of Pharmacology, Vanderbilt University Medical School, Nashville, TN 37232, USA
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Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention. Cancer Metastasis Rev 2012; 30:363-85. [PMID: 22134655 DOI: 10.1007/s10555-011-9324-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways leads to the generation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Eicosanoid expression levels vary during tumor development and progression of a range of malignancies, including colorectal cancer. The actions of these autocoids are also directly influenced by diet, as demonstrated by recent evidence for omega-3 fatty acids in colorectal cancer (CRC) prevention and/or treatment. Eicosanoids regulate CRC development and progression, while inhibition of these pathways has generally been shown to inhibit tumor growth/progression. A progressive sequence of colorectal cancer development has been identified, ranging from normal colon, to colitis, dysplasia, and carcinoma. While both COX and LOX inhibition are both promising candidates for colorectal cancer prevention and/or treatment, there is an urgent need to understand the mechanisms through which these signalling pathways mediate their effects on tumorigenesis. This will allow identification of safer, more effective strategies for colorectal cancer prevention and/or treatment. In particular, binding to/signalling through prostanoid receptors have recently been the subject of considerable interest in this area. In this review, we discuss the role of the eicosanoid signalling pathways in the development and progression of colorectal cancer. We discuss the effects of the eicosanoids on tumor cell proliferation, their roles in cell death induction, effects on angiogenesis, migration, invasion and their regulation of the immune response. Signal transduction pathways involved in these processes are also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of colorectal cancer are outlined.
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Abstract
Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to an increased risk of tumorigenesis and tumor cell invasiveness. Various bioactive lipids, particularly those formed by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, have been well established as therapeutic targets for many epithelial cancers. Emerging studies suggest that there is a role for anti-inflammatory bioactive lipids and their mediators during the resolution phase of inflammation. These proresolving bioactive lipids, including lipoxins (LXs) and resolvins (RVs), have potent anti-inflammatory and anti-carcinogenic properties. The molecular signaling pathways controlling generation and degradation of the proresolving mediators LXs and RVs are now being elucidated, and the component molecules may serve as new targets for regulation of inflammation and inflammation-associated cancers like colon and pancreatic cancers. This review will highlight the recent advances in our understanding of how these bioactive lipids and proresolving mediators may function with various immune cells and cytokines in inhibiting tumor cell proliferation and progression and invasiveness of colon and pancreatic cancers.
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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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Prijatelj M, Celhar T, Gobec M, Mlinaric-Rascan I. EP4 receptor signalling in immature B cells involves cAMP and NF-κB dependent pathways. ACTA ACUST UNITED AC 2012; 64:1090-8. [PMID: 22775212 DOI: 10.1111/j.2042-7158.2012.01499.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Delineation of EP4 receptor signalling properties in immature B cells. METHODS WEHI 231 cells were used as a model of immature B lymphocytes. The effects of PGE2, EP4 receptor antagonist, EP4 receptor agonist, forskolin and adenylate cyclase inhibitor on proliferation of WEHI 231 cells were examined by MTS assay. Cyclic adenosine monophosphate (cAMP) levels were examined by ELISA, whereas phosphorylation of vasodilator-stimulated phosphoprotein (VASP), kinase, extracellular signal-regulated kinase1/2, IκB-α and nuclear factor (NF)-κB subunit p105 were subjected to Western blot analysis. Translocation of NF-κB subunit p65 and EPRAP (EP4 receptor associated protein) was examined by fluorescence microscopy. Levels of early growth response factor (Egr)-1 mRNA were determined by quantitative PCR. KEY FINDINGS We identified the EP4 receptor as the principal molecule mediating the growth-suppressive effect of prostaglandin E2 in WEHI 231 cells. EP4 receptor activation results in cAMP formation and the activation of protein kinase A, NF-κB1 p105 subunit stabilization and inhibition of IκBα phosphorylation, followed by the accumulation of NF-κB p65 subunit in the cell cytoplasm, whereas the activation of PI3K is not involved in EP4 receptor signalling. Elevation of cAMP and inhibition of NF-κB activation are two possible mechanisms by which the EP4 receptor inhibits the proliferation of immature B lymphocytes. CONCLUSIONS Modulation of the EP4 receptor on immature B lymphocytes provides important insight into the observed action of PGE2 and opens new possibilities for the development of therapies for autoimmune diseases, leukaemia and lymphomas.
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Affiliation(s)
- Matevz Prijatelj
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
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Khan KMF, Kothari P, Du B, Dannenberg AJ, Falcone DJ. Matrix metalloproteinase-dependent microsomal prostaglandin E synthase-1 expression in macrophages: role of TNF-α and the EP4 prostanoid receptor. THE JOURNAL OF IMMUNOLOGY 2012; 188:1970-80. [PMID: 22227567 DOI: 10.4049/jimmunol.1102383] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Matrix metalloproteinase (MMP)-9 contributes to the pathogenesis of chronic inflammatory diseases and cancer. Thus, identifying targetable components of signaling pathways that regulate MMP-9 expression may have broad therapeutic implications. Our previous studies revealed a nexus between metalloproteinases and prostanoids whereby MMP-1 and MMP-3, commonly found in inflammatory and neoplastic foci, stimulate macrophage MMP-9 expression via the release of TNF-α and subsequent induction of cyclooxygenase-2 and PGE(2) engagement of EP4 receptor. In the current study, we determined whether MMP-induced cyclooxygenase-2 expression was coupled to the expression of prostaglandin E synthase family members. We found that MMP-1- and MMP-3-dependent release of TNF-α induced rapid and transient expression of early growth response protein 1 in macrophages followed by sustained elevation in microsomal prostaglandin synthase 1 (mPGES-1) expression. Metalloproteinase-induced PGE(2) levels and MMP-9 expression were markedly attenuated in macrophages in which mPGES-1 was silenced, thereby identifying mPGES-1 as a therapeutic target in the regulation of MMP-9 expression. Finally, the induction of mPGES-1 was regulated, in part, through a positive feedback loop dependent on PGE(2) binding to EP4. Thus, in addition to inhibiting macrophage MMP-9 expression, EP4 antagonists emerge as potential therapy to reduce mPGES-1 expression and PGE(2) levels in inflammatory and neoplastic settings.
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Affiliation(s)
- K M Faisal Khan
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
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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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Oates JA. Cardiovascular Risk Markers and Mechanisms in Targeting the COX Pathway for Colorectal Cancer Prevention. Cancer Prev Res (Phila) 2011; 4:1145-8. [DOI: 10.1158/1940-6207.capr-11-0333] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Lejeune M, Moreau F, Chadee K. Prostaglandin E2 produced by Entamoeba histolytica signals via EP4 receptor and alters claudin-4 to increase ion permeability of tight junctions. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:807-18. [PMID: 21683675 DOI: 10.1016/j.ajpath.2011.05.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 04/25/2011] [Accepted: 05/02/2011] [Indexed: 11/24/2022]
Abstract
Entamoeba histolytica is a protozoan parasite that causes amebic dysentery characterized by severe watery diarrhea. Unfortunately, the parasitic factors involved in the pathogenesis of diarrhea are poorly defined. Prostaglandin E(2) (PGE(2)) is a host lipid mediator associated with diarrheal diseases. Intriguingly, E. histolytica produces and secretes this inflammatory molecule. We investigated the mechanism whereby ameba-derived PGE(2) induces the onset of diarrhea by altering ion permeability of paracellular tight junctions (TJs) in colonic epithelia. PGE(2) decreased barrier integrity of TJs in a dose- and time-dependent manner, as measured by transepithelial resistance. PGE(2) signals were selectively transduced via the EP4 receptor. Furthermore, PGE(2) signaling decreased TJ integrity, as revealed by EP receptor-specific agonist and antagonist studies. Loss of mucosal barrier integrity corresponded with increased ion permeability across TJs. Subcellular fractionation and confocal microscopy studies highlighted a significant spatial alteration of an important TJ protein, claudin-4, that corresponded with increased sodium ion permeability through TJs toward the lumen. Moreover, PGE(2)-induced luminal chloride secretion was a prerequisite for alterations at TJs. Thus, the gradient of NaCl created across epithelia could serve as a trigger for osmotic water flow that leads to diarrhea. Our results highlight a pathological role for E. histolytica-derived PGE(2) in the onset of diarrhea.
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Affiliation(s)
- Manigandan Lejeune
- Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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Catalano RD, Wilson MR, Boddy SC, McKinlay ATM, Sales KJ, Jabbour HN. Hypoxia and prostaglandin E receptor 4 signalling pathways synergise to promote endometrial adenocarcinoma cell proliferation and tumour growth. PLoS One 2011; 6:e19209. [PMID: 21589857 PMCID: PMC3093383 DOI: 10.1371/journal.pone.0019209] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Accepted: 03/22/2011] [Indexed: 12/21/2022] Open
Abstract
The prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG) E(2). PTGS2 expression and PGE(2) biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE(2) regulate endometrial tumour growth is unknown. Here we investigated (a) the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3) and PGE receptors (PTGER1-4) in endometrial adenocarcinomas compared with normal endometrium and (b) the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells) xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE(2) and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE(2) and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells.
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Affiliation(s)
- Rob D. Catalano
- Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Martin R. Wilson
- Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Sheila C. Boddy
- Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew T. M. McKinlay
- Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Kurt J. Sales
- Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Henry N. Jabbour
- Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
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Serafini G, Pompili M, Innamorati M, Giordano G, Tatarelli R, Lester D, Girardi P, Dwivedi Y. Glycosides, depression and suicidal behaviour: the role of glycoside-linked proteins. Molecules 2011; 16:2688-2713. [PMID: 21441870 PMCID: PMC6259655 DOI: 10.3390/molecules16032688] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 03/17/2011] [Accepted: 03/18/2011] [Indexed: 01/19/2023] Open
Abstract
Nowadays depression and suicide are two of the most important worldwide public health problems. Although their specific molecular mechanisms are still largely unknown, glycosides can play a fundamental role in their pathogenesis. These molecules act presumably through the up-regulation of plasticity-related proteins: probably they can have a presynaptic facilitatory effect, through the activation of several intracellular signaling pathways that include molecules like protein kinase A, Rap-1, cAMP, cADPR and G proteins. These proteins take part in a myriad of brain functions such as cell survival and synaptic plasticity. In depressed suicide victims, it has been found that their activity is strongly decreased, primarily in hippocampus and prefrontal cortex. These studies suggest that glycosides can regulate neuroprotection through Rap-1 and other molecules, and may play a crucial role in the pathophysiology of depression and suicide.
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Affiliation(s)
- Gianluca Serafini
- Department of Neuroscience, Mental Health and Sensory Functions, "Sapienza" University of Rome, Suicide Prevention Center, Sant'Andrea Hospital, Via Grottarossa 1035-1039, 00189 Rome, Italy.
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Chandramouli A, Mercado-Pimentel ME, Hutchinson A, Gibadulinová A, Olson ER, Dickinson S, Shañas R, Davenport J, Owens J, Bhattacharyya AK, Regan JW, Pastorekova S, Arumugam T, Logsdon CD, Nelson MA. The induction of S100p expression by the Prostaglandin E₂ (PGE₂)/EP4 receptor signaling pathway in colon cancer cells. Cancer Biol Ther 2010; 10:1056-66. [PMID: 20890108 DOI: 10.4161/cbt.10.10.13373] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Prostaglandin E₂ (PGE₂) levels are frequently elevated in colorectal carcinomas. PGE₂ is perceived via four transmembrane G protein coupled receptors (EP1-4), among which the EP4 receptor is most relevant. PGE₂/EP4-receptor interaction activates CREB via the ERK/MEK pathway. However, the downstream target genes activated by this pathway remained to be investigated. METHODOLOGY/PRINICIPAL FINDINGS Here, we have identified S100P (an EF-hand calcium binding protein) as a novel downstream target. We show by realtime RT-PCR that S100P mRNA levels are elevated in 14/17 (82%) colon tumor tissues as compared to paired adjacent normal colonic tissues. S100P expression is stimulated in the presence of PGE₂ in a time dependent manner at mRNA and protein levels in colon, breast and pancreatic cancer cells. Pharmacological and RNAi-mediated inhibition of the EP4 receptor attenuates PGE₂-dependent S100P mRNA induction. RNA(i)-mediated knockdown of CREB inhibits endogenous S100P expression. Furthermore, using luciferase reporter analysis and EMSA we show that mutation and/or deletion of the CRE sequence within the S100P promoter abolished PGE₂-mediated transcriptional induction. Finally, we demonstrate that RNA(i)-mediated knockdown of S100P compromised invadopodia formation, colony growth and motility of colon cancer cells. Interestingly, endogenous knock down of S100P decreases ERK expression levels, suggesting a role for ERK in regulating S100P mediated cell growth and motility. CONCLUSIONS/SIGNIFICANCE Together, our findings show for the first time that S100P expression is regulated by PGE₂/EP4-receptor signaling and may participate in a feedback signaling that perpetuates tumor cell growth and migration. Therefore, our data suggest that dysregulated S100P expression resulting from aberrant PGE₂/EP4 receptor signaling may have important consequences relevant to colon cancer pathogenesis.
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