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15-Keto prostaglandin E2 induces heme oxygenase-1 expression through activation of Nrf2 in human colon epithelial CCD 841 CoN cells.

Abstract：

:Prostaglandin E2 (PGE2) plays a key role in inflammation-associated carcinogenesis. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of PGE2 to generate 15-keto PGE2. 15-PGDH has been known as a tumor suppressor in various malignancies including colon cancer. However, the molecular mechanisms underlying the tumor-suppressive function of 15-PGDH remain largely unresolved. In this study, we found that 15-keto PGE2 upregulated the expression of heme oxygenase-1 (HO-1), a representative antioxidative and anti-inflammatory enzyme, at both transcriptional and translational levels, in human colon epithelial CCD 841 CoN cells. A redox-sensitive transcription factor, NF-E2-related factor (Nrf2) plays a critical role in the regulation of HO-1 and other cytoprotective proteins. 15-Keto PGE2 induced translocation of Nrf2 into the nucleus and antioxidant response element-driven luciferase activity. Furthermore, the silencing of the Nrf2 gene abolished 15-keto PGE2-induced HO-1 expression in CCD 841 CoN cells. 15-Keto PGE2 activated AKT signaling, and the pharmacological AKT inhibitor, LY294002 suppressed the 15-keto PGE2-induced HO-1 expression. 15-Keto PGE2 generates the reactive oxygen species which is suppressed by the general antioxidant N-acetyl-l-cysteine. N-acetyl-l-cysteine treatment attenuated the 15-keto PGE2-induced phosphorylation of GSK3β, transcriptional activity of Nrf2, and subsequently HO-1 expression. However, 13,14-dihydro-15-keto PGE2 lacking the α,β-unsaturated carbonyl moiety failed to induce intracellular production of reactive oxygen species, HO-1 expression and nuclear translocation of Nrf2. In conclusion, 15-keto PGE2 induces HO-1 expression through Nrf2 activation in human colon epithelial cells.

journal_name

Arch Biochem Biophys

journal_title

Archives of biochemistry and biophysics

authors

Lee JE,Zhong X,Lee JY,Surh YJ,Na HK

doi

10.1016/j.abb.2019.108162

subject

Has Abstract

pub_date

2020-01-15 00:00:00

pages

108162

eissn

0003-9861

issn

1096-0384

pii

S0003-9861(19)30227-9

journal_volume

679

pub_type

杂志文章

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15-Keto prostaglandin E2 induces heme oxygenase-1 expression through activation of Nrf2 in human colon epithelial CCD 841 CoN cells.