Roles of eicosanoids in prostate cancer

Nithipatikom, Kasem; Campbell, William B.

doi:10.2217/17460875.3.4.453

Cited by 15 publications

(9 citation statements)

References 177 publications

(149 reference statements)

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“…In agreement with the reduction of the substrate arachidonic acid in PCa, it has been found that the level of their products (12-and 20-HETE, and PGE2) are higher in the tissue [36,37] and also in urine [38]. These studies along with many others have already shown that the metabolism of arachidonic acid and their products plays an important role in PCa development, and in fact, represents an important therapeutics target (reviewed in [39]). Importantly, our work suggests that the analysis of this metabolite in EVs isolated from urine samples may be used to evaluate in a non-invasive manner what is occurring in prostatic tissue itself in the context of PCa.…”

Section: Discussionmentioning

confidence: 99%

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Clos-García

Loizaga-Iriarte

Zúñiga-García

et al. 2018

J of Extracellular Vesicle

117

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Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultra-high-performance liquid chromatography–mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa.

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Section: Discussionmentioning

confidence: 99%

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Clos-García

Loizaga-Iriarte

Zúñiga-García

et al. 2018

J of Extracellular Vesicle

117

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“…The role of EP receptors in prostate cancer progression, as reviewed by Nithipatikom and Campbell [ 43 ], suggested the roles of EP2 and EP4 in tumor progression. In support, EP4 over-expression in prostatic carcinoma cells was associated with castration-resistant phenotype, and treatment with an EP4 antagonist demonstrated anti-invasive effects in vitro and halted bone metastasis in tumor-transplanted mice [ 44 ].…”

Section: Cox2/pge2 Mediated Cancer Progressionmentioning

confidence: 99%

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Majumder

Nandi

Omar

et al. 2018

IJMS

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G-protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G-protein). When a ligand binds, the receptor activates the attached G-protein by causing the exchange of Guanosine-5′-triphosphate (GTP) for guanosine diphosphate (GDP). They play a major role in many physiological functions, as well as in the pathology of many diseases, including cancer progression and metastasis. Only a few GPCR members have been exploited as targets for developing drugs with therapeutic benefit in cancer. Present review briefly summarizes the signaling pathways utilized by the EP (prostaglandin E receptor) family of GPCR, their physiological and pathological roles in carcinogenesis, with special emphasis on the roles of EP4 in breast cancer progression. We make a case for EP4 as a promising newer therapeutic target for treating breast cancer. We show that an aberrant over-expression of cyclooxygenase (COX)-2, which is an inflammation-associated enzyme, occurring in 40–50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune cells, such as Natural Killer (NK) and T cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis, due to upregulation of multiple angiogenic factors including Vascular Endothelial Growth Factor (VEGF)-A, increased lymphangiogenesis (due to upregulation of VEGF-C/D), and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All of these events were primarily mediated by activation of the Prostaglandin (PG) E receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all of these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs—miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients for monitoring SLC-ablative therapies, such as with EP4A. We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers, such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents, such as inhibitors of programmed cell death (PD)-1 or PD-L1.

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“…Most of the LCFAs described in this study are AA precursors that in turn fuel this pathway. Eicosanoid metabolism produces a variety of molecules with reported tumorogenic activity in prostate cancer [ 42 ]. Importantly, these processes are predicted to occur in the lysosome, in which is reported that may produce pro-oncogenic alterations [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Model-driven discovery of long-chain fatty acid metabolic reprogramming in heterogeneous prostate cancer cells

et al. 2018

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Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal-transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria.

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Roles of eicosanoids in prostate cancer

Cited by 15 publications

References 177 publications

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Model-driven discovery of long-chain fatty acid metabolic reprogramming in heterogeneous prostate cancer cells

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