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15-Deoxy-Δ^12,14-prostaglandin J₂ Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.

ABSTRACT: There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ₂ as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ₂ during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ₂.

SUBMITTER: Kim EH

PROVIDER: S-EPMC8002112 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Abnormal upregulation of prostaglandin E2 (PGE2) is considered to be a key oncogenic event in the development and progression of inflammation-associated human colon cancer. It has been reported that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme catabolizing PGE2, is ubiquitously downregulated in human colon cancer. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ ligand, has been shown to have anticarcinogenic activities. In this study, we investigate the effect of 15d-PGJ2 on expression of 15-PGDH in human colon cancer HCT116 cells. Methods:HCT116 cells were treated with 15d-PGJ2 analysis. The expression of 15-PGDH in the treated cells was measured by Western blot analysis and RT-PCR. In addition, the cells were subjected to a 15-PGDH activity assay. To determine which transcription factor(s) and signaling pathway(s) are involved in 15d-PGJ2-induced 15-PGDH expression, we performed a cDNA microarray analysis of 15d-PGJ2-treated cells. The DNA binding activity of AP-1 was measured by an electrophoretic mobility shift assay. To determine whether the AP-1 plays an important role in the 15d-PGJ2-induced 15-PGDH expression, the cells were transfected with siRNA of c-Jun, a major subunit of AP-1. To elucidate the upstream signaling pathways involved in AP-1 activation by 15d-PGJ2, we examined its effect on phosphorylation of Akt by Western blot analysis in the presence or absence of kinase inhibitor. Results:15d-PGJ2 (10 μM) significantly upregulated 15-PGDH expression at the mRNA and protein levels in HCT-116 cells. 15-PGDH activity was also elevated by 15d-PGJ2. We observed that genes encoding C/EBP delta, FOS-like antigen 1, c-Jun, and heme oxygenase-1 (HO-1) were most highly induced in the HCT116 cells following 15d-PGJ2 treatment. 15d-PGJ2 increased the DNA binding activity of AP-1. Moreover, transfection with specific siRNA against c-Jun significantly reduced 15-PGDH expression induced by 15d-PGJ2. 15d-PGJ2 activates Akt and a pharmacological inhibitor of Akt, LY294002, abrogated 15d-PGJ2-induced 15-PGDH expression. We also observed that an inhibitor of HO-1, zinc protoporphyrin IX, also abrogated upregulation of 15-PGDH and down-regulation of cyclooxygenase-2 expression induced by 15d-PGJ2. Conclusions:These finding suggest that 15d-PGJ2 upregulates the expression of 15-PGDH through AP-1 activation in colon cancer HCT116 cells.

Project description:15-deoxy-?(12,14)-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-?. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin.

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15-Deoxy-Δ^12,14-prostaglandin J₂ Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.

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15-Deoxy-Δ12,14-prostaglandin J2 Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.

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OmicsDI is part of the ELIXIR infrastructure

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15-Deoxy-Δ^12,14-prostaglandin J₂ Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.