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Arch Biochem Biophys. 2019 Oct 26:108162. doi: 10.1016/j.abb.2019.108162. [Epub ahead of print]

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

Author information

1
Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, 01133, Republic of Korea.
2
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
3
Department of Food and Nutrition, College of Health & Wellness, Sungshin Women's University, Seoul, 01133, Republic of Korea.
4
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea.
5
Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, 01133, Republic of Korea. Electronic address: nhkdec28@gmail.com.

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 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.

KEYWORDS:

15-Keto PGE(2); Colon; Heme oxygenase-1; Nrf2; ROS

PMID:
31669540
DOI:
10.1016/j.abb.2019.108162

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