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-Δ12,14-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.
Highlights
Heme oxygenase-1 (HO-1) catalyzes the conversion of heme to carbon monoxide (CO)and bilirubin with a concurrent release of iron
For the comparison of transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2), MCF-7 cells were plated at a confluence of 60% in 6-well plate and grown in RPMI supplemented with 10% heatinactivated fetal bovine serum (FBS) at 37 ◦ C in a humidified atmosphere of 5% CO2 /95% air
We examined the functional role of NRF2 in 15d-PGJ2 -mediated HO-1 expression. siRNA silencing of NRF2 attenuated HO-1 expression (Figure 5F)
Summary
Heme oxygenase-1 (HO-1) catalyzes the conversion of heme to carbon monoxide (CO). and bilirubin with a concurrent release of iron. Pharmacological HO-1 inducers and selective overexpression of HO-1 by genetic manipulation confer anti-inflammatory and other cytoprotective effects in cultured cells and in a variety of animal models of various diseases [6]. 15d-PGJ2 was found to stimulate the expression of VEGF in endothelial cells, human androgen-independent PC3 prostate cancer cells, and the 5637 urinary bladder carcinoma cell line [23,24]. 15d-PGJ2 was previously reported to induce the expression of HO-1 in MCF-7 human breast cancer cells [28]. The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor responsible for maintenance of cellular redox balance by inducing antioxidant and other cytoprotective gene expression [29]. We report that 15d-PGJ2 induces VEGF expression and angiogenesis in human breast cancer cells through Nrf2-mediated upregulation of HO-1
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