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Lyothier I, Diethelm S, Pothier J, Sifferlen T, Pozzi D, Richard-Bildstein S, Siendt H, Fretz H, Boss C, Wyder L, Jeay S, de Kanter R, Gnerre C, Lehembre F, Meyer DS, Corminboeuf O. Discovery of Novel Aminopyrimidines as Selective EP2 Receptor Antagonists. ChemMedChem 2025:e2500119. [PMID: 40192484 DOI: 10.1002/cmdc.202500119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/30/2025] [Indexed: 04/19/2025]
Abstract
EP2 is a G-protein coupled receptor that is activated by prostaglandin E2 (PGE2). Signaling through the EP2 receptor has been shown to play a key role in various processes involved in diseases such as immune disorders or cancer. A new class of selective EP2 antagonists with an attractive in vitro and in vivo profile has been identified. The amide bond in the original screening hit is replaced by various alternatives. The introduction of an aminopyrimidine scaffold results in excellent potency. Improvement of physicochemical and ADME properties is achieved by incorporation of a carboxylic acid moiety, resulting in lead compound 29 exhibiting drug-like properties.
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Affiliation(s)
- Isabelle Lyothier
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Stefan Diethelm
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Julien Pothier
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Thierry Sifferlen
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Davide Pozzi
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Sylvia Richard-Bildstein
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Hervé Siendt
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Heinz Fretz
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Christoph Boss
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Lorenza Wyder
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Sébastien Jeay
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Ruben de Kanter
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Carmela Gnerre
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - François Lehembre
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Dominique S Meyer
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Olivier Corminboeuf
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
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Lyothier I, Diethelm S, Pothier J, Sifferlen T, Pozzi D, Richard-Bildstein S, Siendt H, Fretz H, Boss C, Wyder L, Jeay S, de Kanter R, Gnerre C, Lehembre F, Meyer DS, Corminboeuf O. Discovery of ACT-1002-4271 as a Dual Prostaglandin E2 Receptor 2/Prostaglandin E2 Receptor 4 Antagonist with In Vivo Anti-Tumor Efficacy. ChemMedChem 2025:e2500120. [PMID: 40192498 DOI: 10.1002/cmdc.202500120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/30/2025] [Indexed: 04/22/2025]
Abstract
Prostaglandin E2 (PGE2) signaling via receptors prostaglandin E2 receptor 2 (EP2) and prostaglandin E2 receptor 4 (EP4) is involved in various aspects of cancer and has been shown to promote tumor progression, metastasis, and immune evasion. Inhibition of PGE2 signaling by blockade of the EP2 and EP4 receptors has the potential to counteract the tumor-promoting effects of PGE2. Herein, the discovery of compound 30 (ACT-1002-4271), a dual EP2/EP4 antagonist with single-digit nanomolar potency on both receptors, is presented. The medicinal chemistry strategy is based on fine-tuning of the substitution pattern on an EP2 selective starting point to achieve dual EP2/EP4 antagonism. ACT-1002-4271 demonstrated significant antitumor efficacy in an experimental mammary tumour-6 mouse model when administered subcutaneously.
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Affiliation(s)
- Isabelle Lyothier
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Stefan Diethelm
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Julien Pothier
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Thierry Sifferlen
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Davide Pozzi
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Sylvia Richard-Bildstein
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Hervé Siendt
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Heinz Fretz
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Christoph Boss
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Lorenza Wyder
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Sébastien Jeay
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Ruben de Kanter
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Carmela Gnerre
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - François Lehembre
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Dominique S Meyer
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
| | - Olivier Corminboeuf
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland
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3
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Tredicine M, Mucci M, Recchiuti A, Mattoscio D. Immunoregulatory mechanisms of the arachidonic acid pathway in cancer. FEBS Lett 2025; 599:927-951. [PMID: 39973474 PMCID: PMC11995684 DOI: 10.1002/1873-3468.70013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 01/10/2025] [Accepted: 01/27/2025] [Indexed: 02/21/2025]
Abstract
The arachidonic acid (AA) pathway promotes tumor progression by modulating the complex interactions between cancer and immune cells within the microenvironment. In this Review, we summarize the knowledge acquired thus far concerning the intricate mechanisms through which eicosanoids either promote or suppress the antitumor immune response. In addition, we will discuss the impact of eicosanoids on immune cells and how they affect responsiveness to immunotherapy, as well as potential strategies for manipulating the AA pathway to improve anticancer immunotherapy. Understanding the molecular pathways and mechanisms underlying the role played by AA and its metabolites in tumor progression may contribute to the development of more effective anticancer immunotherapies.
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Affiliation(s)
- Maria Tredicine
- Department of Medical, Oral and Biotechnological SciencesUniversity of Chieti‐PescaraItaly
- Center for Advanced Studies and TechnologyUniversity of Chieti‐PescaraItaly
| | - Matteo Mucci
- Department of Medical, Oral and Biotechnological SciencesUniversity of Chieti‐PescaraItaly
- Center for Advanced Studies and TechnologyUniversity of Chieti‐PescaraItaly
| | - Antonio Recchiuti
- Department of Medical, Oral and Biotechnological SciencesUniversity of Chieti‐PescaraItaly
- Center for Advanced Studies and TechnologyUniversity of Chieti‐PescaraItaly
| | - Domenico Mattoscio
- Department of Medical, Oral and Biotechnological SciencesUniversity of Chieti‐PescaraItaly
- Center for Advanced Studies and TechnologyUniversity of Chieti‐PescaraItaly
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Pang Y, Wang C, Zhang YZ, Wang Z, Imoto S, Lee TY. STForte: tissue context-specific encoding and consistency-aware spatial imputation for spatially resolved transcriptomics. Brief Bioinform 2025; 26:bbaf174. [PMID: 40254832 DOI: 10.1093/bib/bbaf174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/06/2025] [Accepted: 03/17/2025] [Indexed: 04/22/2025] Open
Abstract
Encoding spatially resolved transcriptomics (SRT) data serves to identify the biological semantics of RNA expression within the tissue while preserving spatial characteristics. Depending on the analytical scenario, one may focus on different contextual structures of tissues. For instance, anatomical regions reveal consistent patterns by focusing on spatial homogeneity, while elucidating complex tumor micro-environments requires more expression heterogeneity. However, current spatial encoding methods lack consideration of the tissue context. Meanwhile, most developed SRT technologies are still limited in providing exact patterns of intact tissues due to limitations such as low resolution or missed measurements. Here, we propose STForte, a novel pairwise graph autoencoder-based approach with cross-reconstruction and adversarial distribution matching, to model the spatial homogeneity and expression heterogeneity of SRT data. STForte extracts interpretable latent encodings, enabling downstream analysis by accurately portraying various tissue contexts. Moreover, STForte allows spatial imputation using only spatial consistency to restore the biological patterns of unobserved locations or low-quality cells, thereby providing fine-grained views to enhance the SRT analysis. Extensive evaluations of datasets under different scenarios and SRT platforms demonstrate that STForte is a scalable and versatile tool for providing enhanced insights into spatial data analysis.
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Affiliation(s)
- Yuxuan Pang
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Chunxuan Wang
- School of Data Science, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), 2001 Longxiang Road, Longgang, Shenzhen, 518172, China
| | - Yao-Zhong Zhang
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Zhuo Wang
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), 2001 Longxiang Road, Longgang, Shenzhen, 518172, China
- School of Medicine, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), 2001 Longxiang Road, Longgang, Shenzhen, 518172, China
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Tzong-Yi Lee
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, No. 75 Bo-Ai Street, Hsinchu 300, Taiwan
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Nasry WHS, Rodriguez-Lecompte JC, Martin CK. In vitro expression of genes encoding HIF1α, VEGFA, PGE2 synthases, and PGE2 receptors in feline oral squamous cell carcinoma. J Vet Diagn Invest 2025; 37:223-233. [PMID: 39930728 PMCID: PMC11811947 DOI: 10.1177/10406387251315677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Feline oral squamous cell carcinoma (FOSCC) is an aggressive tumor with poor outcomes. Mechanisms of prostaglandin E2 (PGE2)-related inflammation and angiogenesis interact in human OSCC; however, this relationship has not been reported in FOSCC, to our knowledge. We aimed to characterize expression of genes encoding PGE2 synthases (PTGES1-3), PGE2 receptors (EP1-4), hypoxia inducible factor 1α (HIF1A), and vascular and endothelial growth factor A (VEGFA) in FOSCC cell lines (SCCF1-3) in vitro using reverse-transcription quantitative real-time PCR (RT-qPCR). Expression of PTGES1, PTGES3, EP4, and VEGFA were serum-inducible in SCCF2 cells; VEGFA was also inducible in SCCF1 cells (p ≤ 0.05). Compared to other serum-treated cells, SCCF3 cells had the lowest VEGFA expression despite the highest HIF1A (p ≤ 0.05) expression. PGE2 (5 µg/mL and 35 µg/mL) was added to SCCF2 cells for 4 different times (30, 60, 120, 240 min). Both doses of PGE2 stimulated expression of HIF1A and CD147 at 240 min (p ≤ 0.05). PGE2 treatment stimulated cyclooxygenase 2 (COX2) expression at 30 min, followed by suppression at 60 and 120 min and a sharp reduction in EP4 expression at 60 min (p ≤ 0.05). Treatment of SCCF2 with PGE2 and EP4 antagonist L-161,982 increased COX2 expression, and L-161,982 (alone and in combination with PGE2) stimulated EP4 expression (p ≤ 0.05). Genes for PGE2 synthase enzymes, PGE2 receptors, HIF1α and VEGFA were expressed in FOSCC cells in vitro. SCCF2 cells responded to exogenous PGE2 and EP4 antagonism, suggesting that EP4 activity in FOSCC deserves more study.
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Affiliation(s)
- Walaa Hamed Shaker Nasry
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Juan Carlos Rodriguez-Lecompte
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Chelsea K. Martin
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
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Cheng X, Wang W, Dong M, Cheng J, Zuo J, Zhou X, Wang L, Song L. The haemocyte highly-expressed E-type prostanoid receptor regulates TNF expression during immune response of oyster Crassostrea gigas. FISH & SHELLFISH IMMUNOLOGY 2025; 157:110108. [PMID: 39742929 DOI: 10.1016/j.fsi.2024.110108] [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: 09/27/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/04/2025]
Abstract
Prostaglandin E2 imparts diverse physiological effects on multiple cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4), among which the EP4 is one of subtypes known to mediate the immune response in mammalian monocytes and macrophages. However, the precise characteristics and functions of EP4 in mollusks remain unclear. In the present study, an EP4 homologue (designated as CgEP4) was identified from oyster Crassostrea gigas. CgEP4 contained a seven-helix transmembrane domain, shared significant homology with its vertebrate homologs, and clustered with EP4s from other Mollusca by phylogenetic analysis. When CgEP4 was transfected and expressed in HEK293 cell line, the concentration of intracellular Ca2+ was significantly increased after treatment with its agonist PGE2, while that of cAMP was not obviously changed. The mRNA transcripts of CgEP4 were dominantly expressed in haemocytes, which was 28.37-fold (p < 0.05) higher than that in hepatopancreas. By immunofluorescence analysis, CgEP4 was found to be mainly expressed in the agranulocyte subpopulation, and CgEP4+ agranulocyte accounted for 18 % of total haemocytes. After Vibrio splendidus stimulation, the mRNA expression of CgEP4 in haemocytes was not obviously changed at the first 12 h, then significantly up-regulated at 24 h, which was 2.7-fold (p < 0.01) of that in control group. After PGE2 treatment in vivo, the phosphorylation of JNK (p-JNK) in haemocytes, but not the phosphorylated ERK (p-ERK), was significantly decreased, which was 0.64-fold (p < 0.05) of that in control group. Simultaneously, the mRNA expression levels of CgTNF-1 and CgTNF-2 in haemocytes dramatically down-regulated, which were 0.06-fold (p < 0.05) and 0.73-fold (p < 0.05) of that in control group at 24 h. When the EP4 antagonist Grapiprant was added with PGE2 treatment in vivo, the p-JNK in haemocytes significantly increased, concomitant with the up-regulation of expressions of CgTNF-1 and CgTNF-2, which were 2.86-fold (p < 0.05) and 1.31-fold (p < 0.05) of that in control group at 24 h. Collectively, these results provides the experimental evidence of a haemocyte highly-expressed EP4 receptor CgEP4 regulating TNFs' expression through MAPK pathway in the innate immune response in C. gigas, and it could be used as a surface marker to type and sort a subset of agranulocyte subpopulation among haemocytes.
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Affiliation(s)
- Xuemei Cheng
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Weilin Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Miren Dong
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Junlei Cheng
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Jiajun Zuo
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Xiaoxu Zhou
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
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Képes Z, Szabó JP, Kálmán-Szabó I, Sass T, Esze R, Opposits G, Jószai I, Szikra D, Fenyvesi F, Hajdu I, Trencsényi G. 52Mn-labelled Beta-cyclodextrin for Melanoma Imaging: A Proof-of-concept Preclinical Study. In Vivo 2024; 38:2591-2600. [PMID: 39477386 PMCID: PMC11535897 DOI: 10.21873/invivo.13735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND/AIM As prostaglandin E2 (PGE2) and its receptors (EP2) are over-expressed on tumor cells and microenvironment, radiolabeled cyclodextrins targeting such biomolecules are valuable vector candidates in molecular cancer diagnostics. Using experimental melanoma models, we evaluated the in vivo imaging behavior of novel Manganese-52-labeled (52Mn) randomly methylated beta-cyclodextrin ([52Mn]Mn-DOTAGA-RAMEB) and compared it with the following well-established tumor-specific probes: melanocortin-1 receptor (MC1-R)-affine [68Ga]Ga-DOTA-NAPamide and PGE2 selective [68Ga]Ga-DOTAGA-RAMEB cyclodextrin. MATERIALS AND METHODS Post-injection of [68Ga]Ga-DOTA-NAPamide, [68Ga]Ga-DOTAGA-RAMEB, and [52Mn]Mn-DOTAGA-RAMEB into MC1-R positive B16F10 melanoma-bearing mice, tumor radio-pharmaceutical uptake was quantified in vivo and ex vivo using preclinical positron emission tomography (PET) and high-performance gamma counter. RESULTS Although all tracers performed well in tumor identification, the highest standardized uptake values were detected in the [68Ga]Ga-DOTA-NAPamide scans. Corresponding to the ex vivo data, meaningful [52Mn]Mn-DOTAGA-RAMEB accumulation 1 h post-injection confirmed the tumor-targeting potential of the tracer. Temporal changes in PGE2/EP2 expression of the neoplasms may explain the significant differences observed between the tumor uptake of the two cyclodextrin probes and that of the 52Mn-labelled compound measured 1 h, 4 h, and 3 days post-injection (p≤0.01, p≤0.05). CONCLUSION Although further pharmacokinetical optimization may be required, 52Mn-labelled cyclodextrin holds potential in melanoma diagnostics and the PET-based longitudinal assessment of tumor-associated PGE2/EP2 expression.
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Affiliation(s)
- Zita Képes
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Judit P Szabó
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ibolya Kálmán-Szabó
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamás Sass
- Department of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Regina Esze
- Division of Metabolic Diseases, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gábor Opposits
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - István Jószai
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Dezső Szikra
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ferenc Fenyvesi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
| | - István Hajdu
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - György Trencsényi
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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8
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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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Joshi R, Paracha TU, Mostafa MM, Thorne AJ, Jayasinghe V, Yan D, Hamed O, Newton R, Giembycz MA. Comparison of the Genomic Activity of an EP 4-Receptor and β 2-Adrenoceptor Agonist in BEAS-2B Human Bronchial Epithelial Cells: In Search of Compartmentalized, cAMP-Dependent Gene Expression. J Pharmacol Exp Ther 2024; 391:64-81. [PMID: 39060164 DOI: 10.1124/jpet.124.002226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
It has been proposed that inhaled E-prostanoid 4 (EP4)-receptor agonists could represent a new class of bronchodilators for the treatment of asthma that are as effective as β 2-adrenoceptor agonists. However, the genomic impact of such drugs is unknown despite being potentially deleterious to respiratory health. Herein, we used mRNA-seq to compare the transcriptomic responses produced by 2-[3-[(1R,2S,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxo-cyclopentyl]sulphanylpropylsulphanyl] acetic acid (ONO-AE1-329; an EP4-receptor agonist) and vilanterol (a β 2-adrenoceptor agonist) in BEAS-2B human airway epithelial cells. We also determined if an increase in cAMP mediated by different G protein-coupled receptors (GPCRs) promoted distinct transcriptional signatures by expanding this inquiry to include the adenosine A2B- and I-prostanoid receptor agonists, 2-[[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide (Bay60-6583) and taprostene, respectively. Maximally-effective concentrations of ONO-AE1-329 and vilanterol significantly regulated (q ≤ 0.05; ≥1.5-/≤0.67-fold) 232 and 320 genes, respectively of which 217 were shared. Spearman analysis showed these gene expression changes to be highly rank order correlated, indicating that the functional overlap between the two interventions should be considerable. Unexpectedly, the genomic effects of ONO-AE1-329, vilanterol, Bay 60-6583, and taprostene were also highly rank order correlated. This finding suggests that cAMP generated by any GPCR would initiate the same transcriptional program. Nevertheless, relative to vilanterol, ONO-AE1-329 typically behaved as a partial agonist that varied across transcripts. These data indicate that each ONO-AE1-329-regulated gene differs in sensitivity to cAMP and is defined by a unique receptor occupancy-response relationship. Moreover, if this relatively modest genomic response in BEAS-2B cells is retained in vivo, then inhaled EP4-receptor agonists could represent an alternative, and possibly safer, class of bronchodilators. SIGNIFICANCE STATEMENT: The genomic consequences of β 2-adrenoceptor agonists in asthma are often overlooked despite being potentially harmful to lung health. We determined that ONO-AE1-329, an EP4-receptor agonist and effective bronchodilator, produced gene expression changes in BEAS-2B cells that were typically modest relative to the β 2-adrenoceptor agonist vilanterol. Furthermore, ONO-AE1-329 behaved as a partial agonist that varied across transcripts. If this genomic activity is reproduced in vivo, then EP4-receptor agonists could represent an alternative, and possibly safer, class of bronchodilators.
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Affiliation(s)
- Radhika Joshi
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Tamkeen U Paracha
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mahmoud M Mostafa
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Andrew J Thorne
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Varuna Jayasinghe
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Dong Yan
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Omar Hamed
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Robert Newton
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mark A Giembycz
- Lung Health Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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10
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Zafar HS, Akbar H, Xu H, Ponnuraj N, Van Etten K, Jarosinski KW. Oncogenic Animal Herpesviruses. Curr Opin Virol 2024; 67:101424. [PMID: 38981163 DOI: 10.1016/j.coviro.2024.101424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/26/2024] [Accepted: 06/19/2024] [Indexed: 07/11/2024]
Abstract
Oncogenic viruses play a pivotal role in oncology due to their unique role in unraveling the complexities of cancer development. Understanding the role viruses play in specific cancers is important to provide basic insights into the transformation process, which will help identify potential cellular targets for treatment. This review discusses the diverse role of animal herpesviruses in initiating and promoting various forms of cancer. We will summarize the mechanisms that underlie the development of animal herpesvirus-induced cancer that may provide a basis for developing potential therapeutic interventions or preventative strategies in the future.
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Affiliation(s)
- Hafiz S Zafar
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Haji Akbar
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Huai Xu
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Nagendraprabhu Ponnuraj
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Kathrine Van Etten
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Keith W Jarosinski
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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11
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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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12
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Ermini E, Brai A, Cini E, Finetti F, Giannini G, Padula D, Paradisi L, Poggialini F, Trabalzini L, Tolu P, Taddei M. A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides. Chem Sci 2024; 15:6168-6177. [PMID: 38665538 PMCID: PMC11041255 DOI: 10.1039/d4sc01576b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 03/24/2024] [Indexed: 04/28/2024] Open
Abstract
A stimuli-sensitive linker is one of the indispensable components of prodrugs for cancer therapy as it covalently binds the drug and releases it upon external stimulation at the tumour site. Quinone methide elimination has been widely used as the key transformation to release drugs based on their nucleofugacity. The usual approach is to bind the drug to the linker as a carbamate and release it as a free amine after a self-immolative 1,6-elimination. Although this approach is very efficient, it is limited to amines (as carbamates), alcohols or phenols (as carbonates) or other acidic functional groups. We report here a self-immolative spacer capable of directly linking and releasing amines, phenols, thiols, sulfonamides and carboxyamides after a reductive stimulus. The spacer is based on the structure of (5-nitro-2-pyrrolyl)methanol (NPYM-OH), which was used for the direct alkylation of the functional groups mentioned above. The spacer is metabolically stable and has three indispensable sites for bioconjugation: the bioresponsive trigger, the conjugated 1,6 self-immolative system and a third arm suitable for conjugation with a carrier or other modifiers. Release was achieved by selective reduction of the nitro group over Fe/Pd nanoparticles (NPs) in a micellar aqueous environment (H2O/TPGS-750-M), or by NADH mediated nitroreductase activation. A DFT study demonstrates that, during the 1,6 elimination, the transition state formed from 5-aminopyrrole has a lower activation energy compared to other 5-membered heterocycles or p-aminobenzyl derivatives. The NPYM scaffold was validated by late-stage functionalisation of approved drugs such as celecoxib, colchicine, vorinostat or ciprofloxacin. A hypoxia-activated NPYM-based prodrug (HAP) derived from HDAC inhibitor ST7612AA1 was also produced, which was active in cancer cells under hypoxic conditions.
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Affiliation(s)
- Elena Ermini
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Annalaura Brai
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Elena Cini
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Federica Finetti
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Giuseppe Giannini
- Translational Medicine & Clinical Pharmacology Corporate R&D - Alfasigma SpA Via Pontina, km 30400 00071 Pomezia (Roma) Italy
| | - Daniele Padula
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Lucrezia Paradisi
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Federica Poggialini
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Lorenza Trabalzini
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Paola Tolu
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
| | - Maurizio Taddei
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy
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13
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ZHAO J, ZHU Q, ZHANG Y, LI G, ZHANG Y, LI F, BIAN L. [Role of COX-2/PGE2/EP4 Axis-induced Macrophage Functional Activation
in NSCLC Development]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:245-256. [PMID: 38769827 PMCID: PMC11110263 DOI: 10.3779/j.issn.1009-3419.2024.101.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Indexed: 05/22/2024]
Abstract
BACKGROUND Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. METHODS Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. RESULTS EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. CONCLUSIONS During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC.
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14
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Meng YW, Liu JY. Pathological and pharmacological functions of the metabolites of polyunsaturated fatty acids mediated by cyclooxygenases, lipoxygenases, and cytochrome P450s in cancers. Pharmacol Ther 2024; 256:108612. [PMID: 38369063 DOI: 10.1016/j.pharmthera.2024.108612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/19/2024] [Accepted: 02/05/2024] [Indexed: 02/20/2024]
Abstract
Oxylipins have garnered increasing attention because they were consistently shown to play pathological and/or pharmacological roles in the development of multiple cancers. Oxylipins are the metabolites of polyunsaturated fatty acids via both enzymatic and nonenzymatic pathways. The enzymes mediating the metabolism of PUFAs include but not limited to lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P450s (CYPs) pathways, as well as the down-stream enzymes. Here, we systematically summarized the pleiotropic effects of oxylipins in different cancers through pathological and pharmacological aspects, with specific reference to the enzyme-mediated oxylipins. We discussed the specific roles of oxylipins on cancer onset, growth, invasion, and metastasis, as well as the expression changes in the associated metabolic enzymes and the associated underlying mechanisms. In addition, we also discussed the clinical application and potential of oxylipins and related metabolic enzymes as the targets for cancer prevention and treatment. We found the specific function of most oxylipins in cancers, especially the underlying mechanisms and clinic applications, deserves and needs further investigation. We believe that research on oxylipins will provide not only more therapeutic targets for various cancers but also dietary guidance for both cancer patients and healthy humans.
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Affiliation(s)
- Yi-Wen Meng
- CNTTI of the Institute of Life Sciences & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China
| | - Jun-Yan Liu
- CNTTI of the Institute of Life Sciences & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
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15
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Povo-Retana A, Sánchez-García S, Alvarez-Lucena C, Landauro-Vera R, Prieto P, Delgado C, Martín-Sanz P, Boscá L. Crosstalk between P2Y receptors and cyclooxygenase activity in inflammation and tissue repair. Purinergic Signal 2024; 20:145-155. [PMID: 37052777 PMCID: PMC10997571 DOI: 10.1007/s11302-023-09938-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
The role of extracellular nucleotides as modulators of inflammation and cell stress is well established. One of the main actions of these molecules is mediated by the activation of purinergic receptors (P2) of the plasma membrane. P2 receptors can be classified according to two different structural families: P2X ionotropic ion channel receptors, and P2Y metabotropic G protein-coupled receptors. During inflammation, damaged cells release nucleotides and purinergic signaling occurs along the temporal pattern of the synthesis of pro-inflammatory and pro-resolving mediators by myeloid and lymphoid cells. In macrophages under pro-inflammatory conditions, the expression and activity of cyclooxygenase 2 significantly increases and enhances the circulating levels of prostaglandin E2 (PGE2), which exerts its effects both through specific plasma membrane receptors (EP1-EP4) and by activation of intracellular targets. Here we review the mechanisms involved in the crosstalk between PGE2 and P2Y receptors on macrophages, which is dependent on several isoforms of protein kinase C and protein kinase D1. Due to this crosstalk, a P2Y-dependent increase in calcium is blunted by PGE2 whereas, under these conditions, macrophages exhibit reduced migratory capacity along with enhanced phagocytosis, which contributes to the modulation of the inflammatory response and tissue repair.
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Affiliation(s)
- Adrián Povo-Retana
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain.
| | - Sergio Sánchez-García
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
| | - Carlota Alvarez-Lucena
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
| | - Rodrigo Landauro-Vera
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
| | - Patricia Prieto
- Departamento de Farmacología, Farmacognosia y Botánica. Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, 28040, Madrid, Spain
| | - Carmen Delgado
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Melchor Fernández Almagro 6, 28029, Madrid, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Melchor Fernández Almagro 6, 28029, Madrid, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Melchor Fernández Almagro 6, 28029, Madrid, Spain.
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16
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Corminboeuf O, Diethelm S, Zumbrunn C, Lyothier I, Niggli N, Gnerre C, Jeay S, Lehembre F, Boss C. Design of Dual EP2/EP4 Antagonists through Scaffold Merging of Selective Inhibitors. ChemMedChem 2024; 19:e202300606. [PMID: 37983645 DOI: 10.1002/cmdc.202300606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 11/22/2023]
Abstract
Prostaglandin E2 (PGE2) plays a key role in various stages of cancer. PGE2 signals through the EP2 and the EP4 receptors, promoting tumorigenesis, metastasis, and/or immune suppression. Dual inhibition of both the EP2 and the EP4 receptors has the potential to counteract the effect of PGE2 and to result in antitumor efficacy. We herein disclose for the first time the structure of dual EP2/EP4 antagonists. By merging the scaffolds of EP2 selective and EP4 selective inhibitors, we generated a new chemical series of compounds blocking both receptors with comparable potency. In vitro and in vivo profiling suggests that the newly identified compounds are promising lead structures for further development into dual EP2/EP4 antagonists for use in cancer therapy.
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Affiliation(s)
- Olivier Corminboeuf
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Stefan Diethelm
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Cornelia Zumbrunn
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Isabelle Lyothier
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Nadja Niggli
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Carmela Gnerre
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Sébastien Jeay
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - François Lehembre
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Christoph Boss
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland
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17
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Wei D, Birla H, Dou Y, Mei Y, Huo X, Whitehead V, Osei-Owusu P, Feske S, Patafio G, Tao Y, Hu H. PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization. J Neurosci 2024; 44:e0329232023. [PMID: 37952941 PMCID: PMC10851687 DOI: 10.1523/jneurosci.0329-23.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 08/09/2023] [Accepted: 08/29/2023] [Indexed: 11/14/2023] Open
Abstract
Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain.Significance Statement Store-operated calcium channel (SOC) Orai1 is expressed and functional in dorsal root ganglion (DRG) neurons. Whether Orai1 contributes to peripheral sensitization is unclear. The present study demonstrates that Orai1-mediated SOC function is enhanced in DRG neurons under inflammatory conditions. Global and conditional deletion of Orai1 attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity. We also demonstrate that prostaglandin E2 (PGE2) potentiates SOC function in DRG neurons through EP1-mediated signaling pathway. Importantly, we have found that Orai1 deficiency diminishes PGE2-induced SOC function increase and reduces PGE2-induced increase in neuronal excitability and pain hypersensitivity. These findings suggest that Orai1 plays an important role in peripheral sensitization associated with inflammatory pain. Our study reveals a novel mechanism underlying PGE2/EP1-induced peripheral sensitization. Orai1 may serve as a potential target for pathological pain.
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Affiliation(s)
- Dongyu Wei
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
| | - Hareram Birla
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
| | - Yannong Dou
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
| | - Yixiao Mei
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
| | - Xiaodong Huo
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
| | - Victoria Whitehead
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
| | - Patrick Osei-Owusu
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
| | - Stefan Feske
- Department of Pathology, NYU Grossman School of Medicine, New York, New York 10016
| | - Giovanna Patafio
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
| | - Yuanxiang Tao
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
| | - Huijuan Hu
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
- Department of Anesthesiology, Rutgers New Jersey Medical School Newark, Newark, New Jersey 07103
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Lobos-González L, Oróstica L, Díaz-Valdivia N, Rojas-Celis V, Campos A, Duran-Jara E, Farfán N, Leyton L, Quest AFG. Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models. Int J Mol Sci 2023; 24:16947. [PMID: 38069269 PMCID: PMC10707163 DOI: 10.3390/ijms242316947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/20/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023] Open
Abstract
Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag-/- immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.
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Affiliation(s)
- Lorena Lobos-González
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Avenida Lo Plaza 680, Las Condes 7610658, Chile; (L.L.-G.); (E.D.-J.)
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
| | - Lorena Oróstica
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad Diego Portales, Santiago 8370007, Chile
| | - Natalia Díaz-Valdivia
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Victoria Rojas-Celis
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - America Campos
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- CRUK Scotland Institute, Glasgow G61 1BD, UK
| | - Eduardo Duran-Jara
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Avenida Lo Plaza 680, Las Condes 7610658, Chile; (L.L.-G.); (E.D.-J.)
- Subdepartamento Genética Molecular, Instituto de Salud Pública de Chile, Santiago 7780050, Chile
| | - Nicole Farfán
- Cancer and ncRNAs Laboratory, Universidad Andres Bello, Santiago 7550611, Chile;
| | - Lisette Leyton
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Andrew F. G. Quest
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
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Zeng C, Liu J, Zheng X, Hu X, He Y. Prostaglandin and prostaglandin receptors: present and future promising therapeutic targets for pulmonary arterial hypertension. Respir Res 2023; 24:263. [PMID: 37915044 PMCID: PMC10619262 DOI: 10.1186/s12931-023-02559-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH), Group 1 pulmonary hypertension (PH), is a type of pulmonary vascular disease characterized by abnormal contraction and remodeling of the pulmonary arterioles, manifested by pulmonary vascular resistance (PVR) and increased pulmonary arterial pressure, eventually leading to right heart failure or even death. The mechanisms involved in this process include inflammation, vascular matrix remodeling, endothelial cell apoptosis and proliferation, vasoconstriction, vascular smooth muscle cell proliferation and hypertrophy. In this study, we review the mechanisms of action of prostaglandins and their receptors in PAH. MAIN BODY PAH-targeted therapies, such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, activators of soluble guanylate cyclase, prostacyclin, and prostacyclin analogs, improve PVR, mean pulmonary arterial pressure, and the six-minute walk distance, cardiac output and exercise capacity and are licensed for patients with PAH; however, they have not been shown to reduce mortality. Current treatments for PAH primarily focus on inhibiting excessive pulmonary vasoconstriction, however, vascular remodeling is recalcitrant to currently available therapies. Lung transplantation remains the definitive treatment for patients with PAH. Therefore, it is imperative to identify novel targets for improving pulmonary vascular remodeling in PAH. Studies have confirmed that prostaglandins and their receptors play important roles in the occurrence and development of PAH through vasoconstriction, vascular smooth muscle cell proliferation and migration, inflammation, and extracellular matrix remodeling. CONCLUSION Prostacyclin and related drugs have been used in the clinical treatment of PAH. Other prostaglandins also have the potential to treat PAH. This review provides ideas for the treatment of PAH and the discovery of new drug targets.
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Affiliation(s)
- Cheng Zeng
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China
| | - Jing Liu
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China
| | - Xialei Zheng
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China
| | - Xinqun Hu
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China.
| | - Yuhu He
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China.
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Schlicher L, Green LG, Romagnani A, Renner F. Small molecule inhibitors for cancer immunotherapy and associated biomarkers - the current status. Front Immunol 2023; 14:1297175. [PMID: 38022587 PMCID: PMC10644399 DOI: 10.3389/fimmu.2023.1297175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Following the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with intracellular negative regulators of anti-tumor immune responses has emerged in recent years. The main targets for small molecule drugs currently include enzymes of negative feedback loops in signaling pathways of immune cells and proteins that promote immunosuppressive signals within the tumor microenvironment. In the adaptive immune system, negative regulators of T cell receptor signaling (MAP4K1, DGKα/ζ, CBL-B, PTPN2, PTPN22, SHP1), co-receptor signaling (CBL-B) and cytokine signaling (PTPN2) have been preclinically validated as promising targets and initial clinical trials with small molecule inhibitors are underway. To enhance innate anti-tumor immune responses, inhibitory immunomodulation of cGAS/STING has been in the focus, and inhibitors of ENPP1 and TREX1 have reached the clinic. In addition, immunosuppressive signals via adenosine can be counteracted by CD39 and CD73 inhibition, while suppression via intratumoral immunosuppressive prostaglandin E can be targeted by EP2/EP4 antagonists. Here, we present the status of the most promising small molecule drug candidates for cancer immunotherapy, all residing relatively early in development, and the potential of relevant biomarkers.
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Affiliation(s)
- Lisa Schlicher
- Cancer Cell Targeted Therapy, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland
| | - Luke G. Green
- Therapeutic Modalities, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland
| | - Andrea Romagnani
- Cancer Cell Targeted Therapy, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland
| | - Florian Renner
- Cancer Cell Targeted Therapy, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland
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Xie W, Zhang C, Gao Q, Liu Y, Zhang H, Weng Q. Seasonal expressions of COX-1, COX-2, and EP4 in the scent glands of muskrats ( Ondatra zibethicus). Am J Physiol Regul Integr Comp Physiol 2023; 325:R238-R247. [PMID: 37358350 DOI: 10.1152/ajpregu.00113.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 06/27/2023]
Abstract
Prostaglandins (PGs) serve as signaling molecules that regulate various physiological processes, including inflammation, immune response, blood clotting, and reproduction. The aim of this study was to investigate the immunolocalizations and expression patterns of prostaglandin-E2 (PGE2), cyclooxygenase (COX)-1, and COX-2, as well as its receptor subtypes 4 (EP4) in the scent glands of muskrats (Ondatra zibethicus) during the breeding and nonbreeding periods. There were significant seasonal differences in the scent glandular mass, with higher values in the breeding season and relatively low in the nonbreeding season. PGE2, EP4, COX-1, and COX-2 have been immunolocalized in the scent glandular and epithelial cells in both breeding and nonbreeding seasons, whereas no immunostaining was observed in the interstitial cells. The protein and mRNA expression levels of EP4, COX-1, and COX-2 were higher in the scent glands of the breeding season than those of the nonbreeding season. The mean mRNA levels of EP4, COX-1, and COX-2 were positively correlated with the scent glandular weights. The circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), and PGE2, as well as scent glandular PGE2 and dihydrotestosterone (DHT) concentrations, were also significantly higher in the breeding season. In addition, the transcriptomic study in the scent glands identified that differentially expressed genes might be related to fatty carboxylic monocarboxylic acid, steroidogenic-related pathways, and prostanoid metabolic processes. These findings suggested that prostaglandin-E2 might play an essential autocrine or paracrine role in regulating seasonal changes in the scent glandular functions of the muskrats.
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Affiliation(s)
- Wenqian Xie
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Chaoran Zhang
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Qingjing Gao
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Yuning Liu
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Haolin Zhang
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Qiang Weng
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
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22
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Wulan FF, Wahyuningsih TD, Astuti E, Prasetyo N. Towards targeting EGFR and COX-2 inhibitors: comprehensive computational studies on the role of chlorine group in novel thienyl-pyrazoline derivative. J Biomol Struct Dyn 2023; 42:9857-9872. [PMID: 37643080 DOI: 10.1080/07391102.2023.2252915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023]
Abstract
To enhance the effectiveness of chemotherapy and overcome resistance, scientists must develop novel drugs or scaffolds that have a combined effect, such as the inhibition of EGFR and COX-2. This research employed virtual screening techniques, such as docking, and dynamics simulation, to predict chlorinated thienyl-pyrazoline derivatives that inhibit these proteins. The study proposed eleven (11) ligands with binding energies ranging from -7.8 kcal/mol to -8.7 kcal/mol for EGFR and -6.4 kcal/mol to -8.4 kcal/mol for COX-2. Ligands P1 and P11 exhibited the highest binding affinity for both proteins. The results of RMSD, RMSF, RoG, SASA the number of hydrogen bonds, and BAR free binding energy demonstrated the good stability of ligands P1 and P11 when binding to both proteins over 180 ns simulations. In addition, the absorption, distribution, metabolism, excretion, and toxicity properties of the selected ligands were assessed to predict their toxicity and drug likeliness. Based on the results, these compounds can be proposed for further synthesis and in vitro studies.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Fia Fathiana Wulan
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Tutik Dwi Wahyuningsih
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Endang Astuti
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Niko Prasetyo
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia
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Wyrwicz L, Saunders M, Hall M, Ng J, Hong T, Xu S, Lucas J, Lu X, Lautermilch N, Formenti S, Glynne-Jones R. AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer. Radiother Oncol 2023; 185:109669. [PMID: 37054987 DOI: 10.1016/j.radonc.2023.109669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/15/2023]
Abstract
PURPOSE To assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy in either short course (SCRT) or long course radiotherapy (LCRT) settings for those with locally advanced rectal cancer. PATIENTS AND METHODS Twenty-eight subjects with locally advanced rectal cancer participated in this multicenter, open-label, Phase Ib trial. Enrolled subjects received either 250 mg or 500 mg of AN0025 once daily for 10 weeks with either LCRT or SCRT with chemotherapy (7 subjects/group). Participants were assessed for safety/efficacy starting from the first dose of study drug administration and were followed for 2 years. RESULTS No treatment-emergent adverse or serious adverse events meeting dose-limiting criteria were observed, with only 3 subjects discontinuing AN0025 treatment due to adverse events. Twenty-five of 28 subjects completed 10 weeks of AN0025 and adjuvant therapy and were evaluated for efficacy. Overall, 36.0% of subjects (9/25 subjects) achieved a pathological complete response or a complete clinical response, including 26.7% of subjects (4/15 subjects who underwent surgery) who achieved a pathological complete response. A total of 65.4% of subjects had magnetic resonance imaging-confirmed down-staging ≤ stage 3 following completion of treatment. With a median follow-up of 30 months. The 12-month disease-free survival and overall survival were 77.5% (95% confidence interval [CI]: 56.6, 89.2) and 96.3% (95% CI: 76.5, 99.5), respectively. CONCLUSIONS Treatment with AN0025 administered for 10 weeks along with preoperative SCRT or LCRT did not appear to worsen the toxicity in subjects with locally advanced rectal cancer, was well-tolerated and showed promise in inducing both a pathological and complete clinical response. These findings suggest its activity deserves further investigation in larger clinical trials.
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Affiliation(s)
- Lucjan Wyrwicz
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
| | - Mark Saunders
- Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Marcia Hall
- Medical Oncology, Mount Vernon Cancer Centre, Northwood, United Kingdom
| | - John Ng
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Theodore Hong
- Massachusetts General Hospital, Harvard Medical School, Hatfield, United Kingdom
| | - Sherry Xu
- Adlai Nortye USA, North Brunswick, NJ, United States
| | - Justin Lucas
- Adlai Nortye USA, North Brunswick, NJ, United States
| | - Xuyang Lu
- Adlai Nortye USA, North Brunswick, NJ, United States
| | | | - Silvia Formenti
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, United States
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Buchholz A, Vattai A, Fürst S, Vilsmaier T, Zati Zehni A, Steger A, Kuhn C, Schmoeckel E, Dannecker C, Mahner S, Jeschke U, Heidegger HH. Prostaglandin E2 receptor EP1 expression in vulvar cancer. J Cancer Res Clin Oncol 2023; 149:5369-5376. [PMID: 36436093 PMCID: PMC10349743 DOI: 10.1007/s00432-022-04487-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/15/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE In recent years, incidence of vulvar cancer has been on the rise, whereas therapeutic options are still restricted. Therefore, new prognosticators and therapeutic targets are essential. Chronic inflammation plays an important role in carcinogenesis and COX-2, and its product prostaglandin E2 and its receptors EP1-4 are known to be important mediators in cancer initiation and progression. METHODS EP1 expression in vulvar cancer specimens (n = 129) was investigated via immunohistochemistry and evaluated using the well-established immunoreactive score (IRS). Subsequently, the values were correlated with clinicopathological parameters. RESULTS Our analysis did not reveal EP1 expression as a negative prognostic factor in overall and disease-free survival. However, in the subgroup of patients with lymph-node metastasis, overall survival was significantly shorter in tumors with high EP1 expression. Moreover, EP1 expression correlated positively with good differentiation of the tumor, but not with p16 status or COX-2 expression. CONCLUSIONS This study shed first light on EP1 expression in vulvar carcinoma. EP1 expression correlated significantly with the grading of the tumor, suggesting that it influences cell differentiation. Further research on EP1 signaling may lead to a deeper understanding of the molecular mechanisms of carcinogenesis.
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Affiliation(s)
- Anna Buchholz
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Aurelia Vattai
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Sophie Fürst
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Theresa Vilsmaier
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Alaleh Zati Zehni
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Alexander Steger
- Klinik und Poliklinik für Innere Medizin I, University Hospital, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany
| | - Christina Kuhn
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Elisa Schmoeckel
- Department of Pathology, LMU Munich, Thalkirchner Str. 142, 80337, Munich, Germany
| | - Christian Dannecker
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany.
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany.
| | - Helene H Heidegger
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
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Xin P, Wang S, Xu X, Liu Q, Zhang C. Natural fulvic acids inhibit non-small-cell lung cancer through the COX-2/PGE2/EP4 axis: In silico and in vivo assessments. Heliyon 2023; 9:e17080. [PMID: 37484418 PMCID: PMC10361232 DOI: 10.1016/j.heliyon.2023.e17080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/25/2023] Open
Abstract
Purpose Non-small-cell lung cancer (NSCLC) is a major public health concern with a high incidence worldwide. Coal-derived fulvic acids (FAs) contain functional groups in their chemical structures. Overexpression of cyclooxygenases-2 (COX-2), prostaglandin E2 (PGE2), and the PGE2 receptor EP4 subtype (EP4) can have a potential link with the increased tumor incidence and promoted tumor growth and metastasis in NSCLC. This study aimed to assess the biological roles of coal-derived FAs in the growth and development of NSCLC and to elucidate the underlying molecular mechanisms. Methods A web-based tool for predicting small-molecule pharmacokinetics (pkCSM) was used to analyze the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of FAs. Molecular docking and dynamic simulations were performed to analyze the binding affinities of COX-2 and EP4 to FA. An acute toxicity test and an antitumor study were used to analyze the toxicity and anti-NSCLC effects of FAs. Thirty NSCLC-bearing nude mice were randomly divided into five groups (six mice per group): vehicle control, positive control with 20 mg/kg body weight (BW) 5-fluorouracil, and three treatments with 25, 50, and 100 mg/kg BW FAs. The BW and tumor volume were recorded, and the COX-2, PGE2, and EP4 protein expression were measured and analyzed. Results Using the predictive pkCSM algorithm, we found that FA did not cause developmental toxicity. Molecular simulations revealed that COX-2 and EP4 expression was inhibited by FA. An acute toxicity test conformed that the maximum tolerated FAs dose was >3.0 g/kg BW. The animal study demonstrated that FA treatment significantly downregulated the expression of COX-2, PGE2, and EP4 in NSCLC-bearing mice compared to that in vehicle control mice (p < 0.01). Conclusions Natural FAs may exert anti-NSCLC effects through the COX-2/PGE2/EP4 axis.
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Affiliation(s)
- Pengfei Xin
- Department of Stomatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shirui Wang
- Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, China
| | - Xin Xu
- Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, China
| | - Qingmei Liu
- Department of Stomatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Caifeng Zhang
- Department of Chemistry, Taiyuan Normal University, Humic Acid Engineering and Technology Research Center of Shanxi Province, Jinzhong, 030619, China
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Gu M, Yu Y, Xue M, Jiang J, Cai J. The discovery of cyclic γ-AApeptides as the promising ligands targeting EP2. Bioorg Med Chem Lett 2023; 87:129255. [PMID: 36965536 PMCID: PMC10141659 DOI: 10.1016/j.bmcl.2023.129255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 03/27/2023]
Abstract
EP2 is a G protein-coupled receptor for prostaglandin E2 (PGE2) derived from cell membrane-released arachidonic acid upon various harmful and injurious stimuli. It is commomly upregulated in tumors and injured brain tissues, as its activation by PGE2 is widely believed to be involved in the pathophysiological mechanisms underlying these conditions via promoting pro-inflammatory reactions. Herein, we report the discovery of two novel macrocyclic peptidomimetics based on the screening of a cyclic γ-AApeptides combinatorial library. These two cyclic γ-AApeptides showed excellent binding affinity with the EP2 protein, and they may lead to the development of novel therapeutic agents and/or molecular probes to modulate the PGE2/EP2 signaling.
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Affiliation(s)
- Meng Gu
- Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, Tampa, FL 33620, USA
| | - Ying Yu
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Menglin Xue
- Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, Tampa, FL 33620, USA
| | - Jianxiong Jiang
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Jianfeng Cai
- Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, Tampa, FL 33620, USA.
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Képes Z, Hajdu I, Fenyvesi F, Trencsényi G. Insights into recent preclinical studies on labelled cyclodextrin-based imaging probes: towards a novel oncological era. Int J Pharm 2023; 640:122978. [PMID: 37121492 DOI: 10.1016/j.ijpharm.2023.122978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/23/2023] [Accepted: 04/18/2023] [Indexed: 05/02/2023]
Abstract
As malignancies remain one of the major health concerns worldwide, increasing focus has been centered around the application of cyclodextrins (CDs) in cancer imaging and therapy due to their outstanding inclusion forming capability. Albeit the physicochemical properties of CDs were intensively elucidated, the spread of their clinical application is limited by the relative paucity of knowledge about their pharmacokinetic profile, especially biodistribution. Studies applying fluorescently- CDs, or CD-based MRI contrast agents revealed much about pharmacokinetics and diagnostic applications; however, derivatives labelled with positron emitters seem superior molecular probes in the investigation of the route of CDs in biological niche. In vivo imaging based on preclinical tumor-bearing model systems are well-suited to evaluate the whole-body distribution of the two most frequently assessed CDs: randomly methylated β-cyclodextrin (RAMEB), and hydroxypropyl-β-cyclodextrin (HPBCD). Exploiting the firm signaling interaction between cancer-related cyclooxygenase-2, prostaglandin E2 (PGE2) and RAS oncoprotein, radioconjugated, PGE2-affine CDs project the establishment of novel imaging probes and therapeutic agents. Currently, we provide an overview of the preclinical studies on CD pharmacokinetics highlighting the significance of the integration of translational discoveries into human patient care.
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Affiliation(s)
- Zita Képes
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
| | - István Hajdu
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Ferenc Fenyvesi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - György Trencsényi
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
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Finetti F, Paradisi L, Bernardi C, Pannini M, Trabalzini L. Cooperation between Prostaglandin E2 and Epidermal Growth Factor Receptor in Cancer Progression: A Dual Target for Cancer Therapy. Cancers (Basel) 2023; 15:cancers15082374. [PMID: 37190301 DOI: 10.3390/cancers15082374] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/15/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and it is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial-mesenchymal transition, angiogenesis, and immune escape. In addition, the expression of the enzymes involved in PGE2 synthesis, cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES1), positively correlates with tumor progression and aggressiveness, clearly indicating the crucial role of the entire pathway in cancer. Moreover, several lines of evidence suggest that the COX2/mPGES1/PGE2 inflammatory axis is involved in the modulation of epidermal growth factor receptor (EGFR) signaling to reinforce the oncogenic drive of EGFR activation. Similarly, EGFR activation promotes the induction of COX2/mPGES1 expression and PGE2 production. In this review, we describe the interplay between COX2/mPGES1/PGE2 and EGFR in cancer, and new therapeutic strategies that target this signaling pathway, to outline the importance of the modulation of the inflammatory process in cancer fighting.
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Affiliation(s)
- Federica Finetti
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Lucrezia Paradisi
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Clizia Bernardi
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Margherita Pannini
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Lorenza Trabalzini
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
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Oktem EK, Aydin B, Gulfidan G, Arga KY. A Transcriptomic and Reverse-Engineering Strategy Reveals Molecular Signatures of Arachidonic Acid Metabolism in 12 Cancers. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:127-138. [PMID: 36800175 DOI: 10.1089/omi.2022.0185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Cancer and arachidonic acid (AA) have important linkages. For example, AA metabolites regulate several critical biological functions associated with carcinogenesis: angiogenesis, apoptosis, and cancer invasion. However, little is known about the comparative changes in metabolite expression of the arachidonic acid pathway (AAP) in carcinogenesis. In this study, we examined transcriptome data from 12 cancers, such as breast invasive carcinoma, colon adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma. We also report here a reverse-engineering strategy wherein we estimated metabolic signatures associated with AAP by (1) making deductive inferences through transcriptome-level data extraction, (2) remodeling AA metabolism, and (3) performing a comparative analysis of cancer types to determine the similarities and differences between different cancer types with respect to AA metabolic alterations. We identified 77 AAP gene signatures differentially expressed in cancers and 37 AAP metabolites associated with them. Importantly, the metabolite 15(S)-HETE was identified in almost all cancers, while arachidonate, 5-HETE, PGF2α, 14,15-EET, 8,9-EET, 5,6-EET, and 20-HETE were discovered as other most regulated metabolites. This study shows that the 12 cancers studied herein, although in different branches of the AAP, have altered expression of AAP gene signatures. Going forward, AA related-cancer research generally, and the molecular signatures and their estimated metabolites reported herein specifically, hold broad promise for precision/personalized medicine in oncology as potential therapeutic and diagnostic targets.
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Affiliation(s)
- Elif Kubat Oktem
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, İstanbul Medeniyet University, Istanbul, Turkey
| | - Busra Aydin
- Department of Bioengineering, Faculty of Engineering and Architecture, Konya Food and Agriculture University, Konya, Turkey
| | - Gizem Gulfidan
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.,Genetic and Metabolic Diseases Research and Investigation Center, Faculty of Medicine, Marmara University, Istanbul, Turkey
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30
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Piperine Reduces Neoplastic Progression in Cervical Cancer Cells by Downregulating the Cyclooxygenase 2 Pathway. Pharmaceuticals (Basel) 2023; 16:ph16010103. [PMID: 36678600 PMCID: PMC9866887 DOI: 10.3390/ph16010103] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/22/2022] [Accepted: 12/27/2022] [Indexed: 01/13/2023] Open
Abstract
Cervical cancer is the fourth-most common type of cancer in the world that causes death in women. It is mainly caused by persistent infection by human papillomavirus (HPV) that triggers a chronic inflammatory process. Therefore, the use of anti-inflammatory drugs is a potential treatment option. The effects of piperine, an amino alkaloid derived from Piper nigrum, are poorly understood in cervical cancer inflammation, making it a target of research. This work aimed to investigate the antitumor effect of piperine on cervical cancer and to determine whether this effect is modulated by the cyclooxygenase 2 (PTGS2) pathway using in vitro model of cervical cancer (HeLa, SiHa, CaSki), and non-tumoral (HaCaT) cell lines. The results showed that piperine reduces in vitro parameters associated with neoplastic evolution such as proliferation, viability and migration by cell cycle arrest in the G1/G0 and G2/M phases, with subsequent induction of apoptosis. This action was modulated by downregulation of cyclooxygenase 2 (PTGS2) pathway, which in turn regulates the secretion of cytokines and the expression of mitogen-activated protein kinases (MAPKs), metalloproteinases (MMPs), and their antagonists (TIMPs). These findings indicate the phytotherapeutic potential of piperine as complementary treatment in cervical cancer.
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31
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Wang W, Liang M, Wang L, Bei W, Rong X, Xu J, Guo J. Role of prostaglandin E2 in macrophage polarization: Insights into atherosclerosis. Biochem Pharmacol 2023; 207:115357. [PMID: 36455672 DOI: 10.1016/j.bcp.2022.115357] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022]
Abstract
Atherosclerosis, a trigger of cardiovascular disease, poses grave threats to human health. Although atherosclerosis depends on lipid accumulation and vascular wall inflammation, abnormal phenotypic regulation of macrophages is considered the pathological basis of atherosclerosis. Macrophage polarization mainly refers to the transformation of macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, which has recently become a much-discussed topic. Increasing evidence has shown that M2 macrophage polarization can alleviate atherosclerosis progression. PGE2 is a bioactive lipid that has been observed to be elevated in atherosclerosis and to play a pro-inflammatory role, yet recent studies have reported that PGE2 promotes anti-inflammatory M2 macrophage polarization and mitigates atherosclerosis progression. However, the mechanisms by which PGE2 acts remain unclear. This review summarizes current knowledge of PGE2 and macrophages in atherosclerosis. Additionally, we discuss potential PGE2 mechanisms of macrophage polarization, including CREB, NF-κB, and STAT signaling pathways, which may provide important therapeutic strategies based on targeting PGE2 pathways to modulate macrophage polarization for atherosclerosis treatment.
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Affiliation(s)
- Weixuan Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong Province, China
| | - Mingjie Liang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong Province, China
| | - Lexun Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong Province, China
| | - Weijian Bei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong Province, China
| | - Xianglu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong Province, China
| | - Jianqin Xu
- Department of Endocrinology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi Province, China.
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, Guangdong Province, China.
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32
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Anand S, Azam Ansari M, Kumaraswamy Sukrutha S, Alomary MN, Anwar Khan A, Elderdery AY. Resolvins Lipid Mediators: Potential Therapeutic Targets in Alzheimer and Parkinson Disease. Neuroscience 2022; 507:139-148. [PMID: 36372297 DOI: 10.1016/j.neuroscience.2022.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022]
Abstract
Inflammation and resolution are highly programmed processes involving a plethora of immune cells. Lipid mediators synthesized from arachidonic acid metabolism play a pivotal role in orchestrating the signaling cascades in the game of inflammation. The majority of the studies carried out so far on inflammation were aimed at inhibiting the generation of inflammatory molecules, whereas recent research has shifted more towards understanding the resolution of inflammation. Owing to chronic inflammation as evident in neuropathophysiology, the resolution of inflammation together with the class of lipid mediators actively involved in its regulation has attracted the attention of the scientific community as therapeutic targets. Both omega-three polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, orchestrate a vital regulatory role in inflammation development. Resolvins derived from these fatty acids comprise the D-and E-series resolvins. A growing body of evidence using in vitro and in vivo models has revealed the pro-resolving and anti-inflammatory potential of resolvins. This systematic review sheds light on the synthesis, specialized receptors, and resolution of inflammation mediated by resolvins in Alzheimer's and Parkinson's disease.
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Affiliation(s)
- Santosh Anand
- Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru, Karnataka, India
| | - Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institutes for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
| | - Sambamurthy Kumaraswamy Sukrutha
- Department of Microbiology, Biotechnology and Food Technology, Jnana Bharathi Campus, Bangalore University, Bengaluru, Karnataka, India
| | - Mohammad N Alomary
- National Centre for Biotechnology, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Saudi Arabia
| | - Anmar Anwar Khan
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abozer Y Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Saudi Arabia
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Kourpa A, Kaiser-Graf D, Sporbert A, Philippe A, Catar R, Rothe M, Mangelsen E, Schulz A, Bolbrinker J, Kreutz R, Panáková D. 15-keto-Prostaglandin E2 exhibits bioactive role by modulating glomerular cytoarchitecture through EP2/EP4 receptors. Life Sci 2022; 310:121114. [DOI: 10.1016/j.lfs.2022.121114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/06/2022] [Accepted: 10/17/2022] [Indexed: 11/05/2022]
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In vivo assessment of tumor targeting potential of 68Ga-labelled randomly methylated beta-cyclodextrin (RAMEB) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) using positron emission tomography. Int J Pharm 2022; 630:122462. [PMID: 36462739 DOI: 10.1016/j.ijpharm.2022.122462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022]
Abstract
Cyclodextrin derivates (CyDs) can form complexes with cyclooxygenase-2 induced tumor promoting prostaglandin E2 (PGE2). Based on our previous observations, 68Ga-labelled CyDs may represent promising radiopharmaceuticals in the positron emission tomography (PET) diagnostics of PGE2 positive tumors. We aimed at evaluating the tumor-targeting potential of 68Ga-NODAGA conjugated randomly methylated beta-cyclodextrin (68Ga-NODAGA-RAMEB) and 2-hydroxypropyl-β-cyclodextrin (68Ga-NODAGA-HPβCD) using in vivo PET imaging with experimental tumor models. Tumor radiopharmaceutical uptake was assessed applying PET and gamma counter in vivo and ex vivo respectively, following the administration of 18FDG, 68Ga-NODAGA-RAMEB or 68Ga-NODAGA-HPβCD via the lateral tail vein to the subsequent tumor-bearing animals: HT1080, A20, PancTu-1, BxPC3, B16-F10, Ne/De and He/De. All investigated tumors were identifiable with both 68Ga-labelled CyDs; however, in vivo results, in correlation with the ex vivo data, revealed that the PGE2 positive BxPC3, A20, Ne/De and He/De tumors presented the highest accumulation. In case of HT1080, A20, B16-F10 tumors significant differences were encountered between the accumulations of both 68Ga-labelled radiopharmaceuticals of the same tumor. Subcutaneously and the orthotopically transplanted Ne/De tumors differed significantly (p ≤ 0.01) regarding tracer uptake. 68Ga-labelled CyDs may open a novel field in the PET diagnostics of PGE2 positive primary tumors and metastases.
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Immunoregulatory signal networks and tumor immune evasion mechanisms: insights into therapeutic targets and agents in clinical development. Biochem J 2022; 479:2219-2260. [DOI: 10.1042/bcj20210233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022]
Abstract
Through activation of immune cells, the immune system is responsible for identifying and destroying infected or otherwise damaged cells including tumorigenic cells that can be recognized as foreign, thus maintaining homeostasis. However, tumor cells have evolved several mechanisms to avoid immune cell detection and killing, resulting in tumor growth and progression. In the tumor microenvironment, tumor infiltrating immune cells are inactivated by soluble factors or tumor promoting conditions and lose their effects on tumor cells. Analysis of signaling and crosstalk between immune cells and tumor cells have helped us to understand in more detail the mechanisms of tumor immune evasion and this forms basis for drug development strategies in the area of cancer immunotherapy. In this review, we will summarize the dominant signaling networks involved in immune escape and describe the status of development of therapeutic strategies to target tumor immune evasion mechanisms with focus on how the tumor microenvironment interacts with T cells.
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36
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Shin VY, Liu MX, Siu JMT, Kwong A, Chu KM. Inhibition of EP2 receptor suppresses tumor growth and chemoresistance of gastric cancer. Am J Cancer Res 2022; 12:4680-4692. [PMID: 36381319 PMCID: PMC9641405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 07/20/2022] [Indexed: 06/16/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer death in the world. Early diagnosis and effective chemotherapy are vital to reduce the overall mortality. Prostaglandin E2 (PGE2) has been implicated as an important factor in gastric cancer carcinogenesis. ECF based regimen (epirubicin, cisplatin, 5-fluorouracil) is the first-line chemotherapy for advanced gastric cancer. However, patients develop resistance after chemotherapy. The aim of this study is sought to investigate the role of EP2 receptor, a PGE2 receptor, and the antagonism of EP2 receptor in response to ECF treatment. Expression of EP2 receptor was evaluated in gastric cancer tissue samples and cell lines. Cell proliferation and cell apoptosis assays were performed in vitro and in vivo, upon knockdown of EP2 receptor, antagonist of EP2 receptor and/or ECF treatment. Western Blot was applied for evaluation of proteins relating to cell cycle, apoptosis and drug transporter. Next generation sequencing and ingenuity pathway analysis were applied for screening for downstream targets of EP2 receptor. Expressions of the targets of EP2 receptor were further evaluated in gastric cancer cells and tissues. In this study, we found that expression of EP2 receptor was significantly upregulated in gastric cancer. Inhibition of EP2 receptor reduced gastric cancer cell proliferation, induced cell cycle arrest proteins, and enhanced cell apoptosis. Moreover, knockdown of EP2 receptor by siRNA or antagonist sensitized gastric cancer cells to ECF. Silence of EP2 receptor also significantly abrogated gastric cancer growth in a mice model. Analysis revealed that CAV1 was a downstream target of EP2 receptor in gastric cancer. Our findings illustrated that blocking EP2 receptor reduced tumor growth and induced apoptosis in gastric cancer. This novel study unraveled CAV1 was a downstream target of EP2 receptor. Antagonizing EP2 receptor could be a potential therapeutic target in gastric cancer, in particular those with high EP2 receptor expression.
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In vivo investigation of Gallium-68 and Bismuth-205/206 labeled beta cyclodextrin for targeted alpha therapy of prostaglandin E2 receptor-expressing tumors in mice. Int J Pharm 2022; 625:122132. [PMID: 36028082 DOI: 10.1016/j.ijpharm.2022.122132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/26/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022]
Abstract
Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with 68Ga and 205/206Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (logP values), and in vitro and in vivo stability were determined. For the assessment of the biological properties and the PGE2 specificity of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB in vivo PET imaging and ex vivo biodistribution studies were performed using healthy control and PGE2-positive BxPC-3 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was higher than 98 %. In vivo studies showed that the tumor-to-background ratio of [68Ga]Ga-DOTAGA-RAMEB was 2.5 ± 0.2 as a result BxPC-3 tumors were clearly identified on PET images. Beside this the ex vivo biodistribution studies showed that the accumulation rate of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was similar in the PGE2-positive BxPC-3 tumors.
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The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics. Cells 2022; 11:cells11162528. [PMID: 36010605 PMCID: PMC9406919 DOI: 10.3390/cells11162528] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/03/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic infection by high-risk human papillomaviruses (HPV) and chronic inflammation are factors associated with the onset and progression of several neoplasias, including cervical cancer. Oncogenic proteins E5, E6, and E7 from HPV are the main drivers of cervical carcinogenesis. In the present article, we review the general mechanisms of HPV-driven cervical carcinogenesis, as well as the involvement of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and downstream effectors in this pathology. We also review the evidence on the crosstalk between chronic HPV infection and PGE2 signaling, leading to immune response weakening and cervical cancer development. Finally, the last section updates the current therapeutic and preventive options targeting PGE2-derived inflammation and HPV infection in cervical cancer. These treatments include nonsteroidal anti-inflammatory drugs, prophylactic and therapeutical vaccines, immunomodulators, antivirals, and nanotechnology. Inflammatory signaling pathways are closely related to the carcinogenic nature of the virus, highlighting inflammation as a co-factor for HPV-dependent carcinogenesis. Therefore, blocking inflammatory signaling pathways, modulating immune response against HPV, and targeting the virus represent excellent options for anti-tumoral therapies in cervical cancer.
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Hou R, Yu Y, Sluter MN, Li L, Hao J, Fang J, Yang J, Jiang J. Targeting EP2 receptor with multifaceted mechanisms for high-risk neuroblastoma. Cell Rep 2022; 39:111000. [PMID: 35732130 PMCID: PMC9282716 DOI: 10.1016/j.celrep.2022.111000] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 04/02/2022] [Accepted: 06/02/2022] [Indexed: 11/29/2022] Open
Abstract
Prostaglandin E2 (PGE2) promotes tumor cell proliferation, migration, and invasion, fostering an inflammation-enriched microenvironment that facilitates angiogenesis and immune evasion. However, the PGE2 receptor subtype (EP1–EP4) involved in neuroblastoma (NB) growth remains elusive. Herein, we show that the EP2 receptor highly correlates with NB aggressiveness and acts as a predominant Gαs-coupled receptor mediating PGE2-initiated cyclic AMP (cAMP) signaling in NB cells with high-risk factors, including 11q deletion and MYCN amplification. Knockout of EP2 in NB cells blocks the development of xenografts, and its conditional knockdown prevents established tumors from progressing. Pharmacological inhibition of EP2 by our recently developed antagonist TG6-129 suppresses the growth of NB xenografts in nude mice and syngeneic allografts in immunocompetent hosts, accompanied by anti-inflammatory, antiangiogenic, and apoptotic effects. This proof-of-concept study suggests that the PGE2/EP2 signaling pathway contributes to NB malignancy and that EP2 inhibition by our drug-like compounds provides a promising strategy to treat this deadly pediatric cancer. Hou et al. discover that prostaglandin receptor EP2 highly correlates with the aggressiveness of neuroblastoma, where it acts as the primary PGE2 receptor mediating cAMP signaling. EP2 deficiency or inhibition suppresses neuroblastoma with high-risk factors including 11q deletion and MYCN amplification, demonstrating EP2 as a promising therapeutic target for neuroblastoma.
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Affiliation(s)
- Ruida Hou
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Ying Yu
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Madison N Sluter
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Lexiao Li
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jiukuan Hao
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Jie Fang
- Department of Surgery, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jun Yang
- Department of Surgery, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jianxiong Jiang
- Department of Pharmaceutical Sciences, Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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40
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Tsai YT, Lo WL, Chen PY, Ko CY, Chuang JY, Kao TJ, Yang WB, Chang KY, Hung CY, Kikkawa U, Chang WC, Hsu TI. Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation. J Biomed Sci 2022; 29:21. [PMID: 35337344 PMCID: PMC8952270 DOI: 10.1186/s12929-022-00804-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/21/2022] [Indexed: 01/10/2023] Open
Abstract
Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. Results Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. Conclusion Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00804-3.
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Affiliation(s)
- Yu-Ting Tsai
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan, 110
| | - Wei-Lun Lo
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.,Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, 110, Taiwan.,TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan
| | - Pin-Yuan Chen
- School of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan.,Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Keelung, 204, Taiwan.,Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Chiung-Yuan Ko
- TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.,Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.,Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan.,Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei, 110, Taiwan
| | - Jian-Ying Chuang
- TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.,Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.,Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan.,Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei, 110, Taiwan
| | - Tzu-Jen Kao
- TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.,Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.,Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan.,Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei, 110, Taiwan
| | - Wen-Bing Yang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan, 110.,TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan
| | - Kwang-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
| | - Chia-Yang Hung
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Ushio Kikkawa
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan, 110
| | - Wen-Chang Chang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan, 110. .,TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.
| | - Tsung-I Hsu
- TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan. .,Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan. .,Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan. .,Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan. .,TMU Research Center of Cancer Translational Medicine, Taipei, 110, Taiwan. .,National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan.
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Rovati G, Contursi A, Bruno A, Tacconelli S, Ballerini P, Patrignani P. Antiplatelet Agents Affecting GPCR Signaling Implicated in Tumor Metastasis. Cells 2022; 11:725. [PMID: 35203374 PMCID: PMC8870128 DOI: 10.3390/cells11040725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 11/16/2022] Open
Abstract
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial-mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A2, and prostaglandin (PG) E2, act through G protein-coupled receptors (GPCRs) to cause the activation of more additional platelets and drive metastatic signaling pathways in cancer cells. In this review, we examine the contribution of the GPCRs of platelets and cancer cells in the development of cancer metastasis. Finally, the possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed.
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Affiliation(s)
- Gianenrico Rovati
- Department of Pharmaceutical Sciences, University of Milan, 20122 Milan, Italy;
| | - Annalisa Contursi
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Annalisa Bruno
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Stefania Tacconelli
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Patrizia Ballerini
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Innovative Technologies in Medicine and Dentistry, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Paola Patrignani
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
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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: 30] [Impact Index Per Article: 7.5] [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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An Y, Yao J, Niu X. The Signaling Pathway of PGE 2 and Its Regulatory Role in T Cell Differentiation. Mediators Inflamm 2021; 2021:9087816. [PMID: 34867083 PMCID: PMC8641993 DOI: 10.1155/2021/9087816] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 02/01/2023] Open
Abstract
Prostaglandin E2 (PGE2) is a lipid mediator derived from the fatty acid arachidonic acid. As an essential inflammatory factor, PGE2 has a critical impact on immune regulation through the prostanoid E (EP) receptor pathway. T cells, including CD4+ and CD8+ T cell subsets, play crucial roles in the adaptive immune response. Previous studies have shown that PGE2 is involved in regulating CD4+ T cell differentiation and inflammatory cytokine production via the EP receptor pathway, thereby affecting the development of diseases mediated by CD4+ T cells. In this review, we summarize the signaling pathway of PGE2 and describe the relationship between PGE2 and T cell differentiation. Hence, this review may provide important evidence for immune therapies and may even promote the development of biomedicines.
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Affiliation(s)
- Yang An
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, 280 South Chongqing Road, Shanghai 200025, China
| | - Jiameng Yao
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, 280 South Chongqing Road, Shanghai 200025, China
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai 200336, China
| | - Xiaoyin Niu
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, 280 South Chongqing Road, Shanghai 200025, China
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45
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An Insight into GPCR and G-Proteins as Cancer Drivers. Cells 2021; 10:cells10123288. [PMID: 34943797 PMCID: PMC8699078 DOI: 10.3390/cells10123288] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/14/2022] Open
Abstract
G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of these receptors to highly specialized transducer proteins, called G-proteins, and initiate multiple signaling pathways. Integration of these intricate networks of signaling cascades leads to numerous biochemical responses involved in diverse pathophysiological activities, including cancer development. While several studies indicate the role of GPCRs in controlling various aspects of cancer progression such as tumor growth, invasion, migration, survival, and metastasis through its aberrant overexpression, mutations, or increased release of agonists, the explicit mechanisms of the involvement of GPCRs in cancer progression is still puzzling. This review provides an insight into the various responses mediated by GPCRs in the development of cancers, the molecular mechanisms involved and the novel pharmacological approaches currently preferred for the treatment of cancer. Thus, these findings extend the knowledge of GPCRs in cancer cells and help in the identification of therapeutics for cancer patients.
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Fu Y, Zou T, Shen X, Nelson PJ, Li J, Wu C, Yang J, Zheng Y, Bruns C, Zhao Y, Qin L, Dong Q. Lipid metabolism in cancer progression and therapeutic strategies. MedComm (Beijing) 2021; 2:27-59. [PMID: 34766135 PMCID: PMC8491217 DOI: 10.1002/mco2.27] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/17/2020] [Accepted: 07/23/2020] [Indexed: 12/24/2022] Open
Abstract
Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune‐associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.
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Affiliation(s)
- Yan Fu
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
| | - Tiantian Zou
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
| | - Xiaotian Shen
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
| | - Peter J Nelson
- Medical Clinic and Policlinic IV Ludwig-Maximilian-University (LMU) Munich Germany
| | - Jiahui Li
- General, Visceral and Cancer Surgery University Hospital of Cologne Cologne Germany
| | - Chao Wu
- Department of General Surgery, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Jimeng Yang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
| | - Christiane Bruns
- General, Visceral and Cancer Surgery University Hospital of Cologne Cologne Germany
| | - Yue Zhao
- General, Visceral and Cancer Surgery University Hospital of Cologne Cologne Germany
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences Fudan University Shanghai China
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Lone AM, Giansanti P, Jørgensen MJ, Gjerga E, Dugourd A, Scholten A, Saez-Rodriguez J, Heck AJR, Taskén K. Systems approach reveals distinct and shared signaling networks of the four PGE 2 receptors in T cells. Sci Signal 2021; 14:eabc8579. [PMID: 34609894 DOI: 10.1126/scisignal.abc8579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Anna M Lone
- Department of Cancer Immunology, Institute of Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.,K.G. Jebsen Centre for Cancer Immunotherapy and K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0317 Oslo, Norway.,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway
| | - Piero Giansanti
- Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, Netherlands.,Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising 85354, Germany
| | - Marthe Jøntvedt Jørgensen
- K.G. Jebsen Centre for Cancer Immunotherapy and K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0317 Oslo, Norway.,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway
| | - Enio Gjerga
- Joint Research Centre for Computational Biomedicine (JRC-Combine), RWTH-Aachen University Hospital, Faculty of Medicine, Aachen 52074, Germany.,Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Bioquant, Heidelberg University, Heidelberg 69120, Germany
| | - Aurelien Dugourd
- Joint Research Centre for Computational Biomedicine (JRC-Combine), RWTH-Aachen University Hospital, Faculty of Medicine, Aachen 52074, Germany.,Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Bioquant, Heidelberg University, Heidelberg 69120, Germany
| | - Arjen Scholten
- Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, Netherlands
| | - Julio Saez-Rodriguez
- Joint Research Centre for Computational Biomedicine (JRC-Combine), RWTH-Aachen University Hospital, Faculty of Medicine, Aachen 52074, Germany.,Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Bioquant, Heidelberg University, Heidelberg 69120, Germany
| | - Albert J R Heck
- Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, Netherlands
| | - Kjetil Taskén
- Department of Cancer Immunology, Institute of Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.,K.G. Jebsen Centre for Cancer Immunotherapy and K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0317 Oslo, Norway.,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway
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El-Ashmawy NE, El-Zamarany EA, Khedr NF, Selim HM, Khedr EG. Inhibition of PKC/MEK pathway suppresses β1-integrin and mitigates breast cancer cells proliferation. Toxicol Rep 2021; 8:1530-1537. [PMID: 34408972 PMCID: PMC8361284 DOI: 10.1016/j.toxrep.2021.07.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
PGE2 enhanced β1- integrin expression via EP1 receptor, PKC, MEK and NfҡB. FOXC2, E2F1 and survivin play a role in PGE2 mediated effect in MCF7 cells. PGE2 enhances breast cancer cell cycle through E2F1, FOXC2, survivin and β integrin. Biochemical mediators of PKC/MEK pathway could be considered as targets for breast cancer treatment. Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.
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Affiliation(s)
| | - Enas A El-Zamarany
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt
| | - Naglaa F Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Hend M Selim
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Eman G Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
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Nuvoli B, Antoniani B, Libener R, Maconi A, Sacconi A, Carosi M, Galati R. Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:257. [PMID: 34404424 PMCID: PMC8369782 DOI: 10.1186/s13046-021-02050-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/23/2021] [Indexed: 01/12/2023]
Abstract
BACKGROUND Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism. METHODS The interaction between COX-2 and CYP19A1 was first investigated on different MPM lines upon PGE2, and COX-2 inhibitor (rofecoxib) treatment by western blot, RT-PCR. The key regulatory pathways involved in the COX-2 and CYP19A1 axis were further studied in MPM cells, after rofecoxib and exemestane (CYP19A1 inhibitor) treatment in monotherapy and in combination, by cell cycle distribution, western blot, and combination index analysis. To explore the role of COX-2/CYP19A1 axis in 3D preclinical models of MPM cells, we analyzed the effect of combination of COX-2 and CYP19A1 inhibitors in mesosphere formation. Immunohistochemical analysis of MPM mesosphere and specimens was utilized to evaluate the involvement of COX-2 on the CYP19A1 activity and the relationship between E2 and COX-2. RESULTS PGE2 or rofecoxib treatment caused in MPM cells an increased or decreased, respectively, CYP19A1 expression at mRNA and protein levels. The effect of rofecoxib and exemestane combination in MPM cell proliferation was synergistic. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for MPM cell lines. Increased expression levels of p53, p21, and p27, downregulation of cyclin D1 and inhibition of Akt activation (pAKT) were also found. The antagonistic effect of rofecoxib and exemestane combination found only in one cell line, was reverted by pretreatment with MK2206, a pAKT inhibitor, indicating pAKT as an actionable mediator in the COX-2-CYP19A1 axis. Reduction of size and sphere-forming efficiency in MPM spheres after treatment with both inhibitor and a decrease in COX-2 and E2 staining was found. Moreover, immunohistochemical analysis of 46 MPM samples showed a significant positive correlation between COX-2 and E2. CONCLUSIONS Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options.
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Affiliation(s)
- Barbara Nuvoli
- grid.417520.50000 0004 1760 5276Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Barbara Antoniani
- grid.417520.50000 0004 1760 5276Anatomy Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Roberta Libener
- Department of Integrated Activities Research and Innovation, SS Antonio and Biagio General Hospital, Alessandria, Italy
| | - Antonio Maconi
- Department of Integrated Activities Research and Innovation, SS Antonio and Biagio General Hospital, Alessandria, Italy
| | - Andrea Sacconi
- grid.417520.50000 0004 1760 5276Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Mariantonia Carosi
- grid.417520.50000 0004 1760 5276Anatomy Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Rossella Galati
- grid.417520.50000 0004 1760 5276Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
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Basile D, Simionato F, Calvetti L, Cappetta A, Pesavento A, Mongillo M, Roviello G, Rosati G, Rossi G, Aprile G. Comparing immunotherapies to other frequently used treatments of gastric cancer. Expert Rev Clin Pharmacol 2021; 14:1221-1232. [PMID: 34114518 DOI: 10.1080/17512433.2021.1938546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Introduction: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.Areas covered: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations.Expert opinion: Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.
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Affiliation(s)
- Debora Basile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Lorenzo Calvetti
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Annalisa Pesavento
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy.,Oncology Unit, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Marta Mongillo
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy.,Oncology Unit, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | | | - Gerardo Rosati
- Medical Oncology, San Carlo General Hospital, Potenza, Italy
| | - Gemma Rossi
- Medical Oncology, San Carlo General Hospital, Potenza, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
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