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.

中文翻译：

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15-酮前列腺素E2通过激活人结肠上皮CCD 841 CoN细胞中的Nrf2诱导血红素加氧酶-1表达。

前列腺素E2（PGE2）在炎症相关的癌变过程中起关键作用。NAD +依赖性15-羟基前列腺素脱氢酶（15-PGDH）催化PGE2的15（S）-羟基氧化，生成15-酮基PGE2。15-PGDH被公认为包括结肠癌在内的各种恶性肿瘤中的肿瘤抑制剂。然而，15-PGDH的肿瘤抑制功能的分子机制仍未解决。在这项研究中，我们发现15酮PGE2在人类结肠上皮CCD 841 CoN细胞中在转录和翻译水平上均上调了血红素加氧酶-1（HO-1）的表达，这是一种代表性的抗氧化和抗炎酶。氧化还原敏感的转录因子NF-E2相关因子（Nrf2）在HO-1和其他细胞保护蛋白的调节中起着关键作用。15-酮PGE2诱导Nrf2易位到核中，并由抗氧化剂响应元件驱动的荧光素酶活性。此外，Nrf2基因的沉默消除了CCD 841 CoN细胞中15-keto PGE2诱导的HO-1表达。15-酮PGE2激活AKT信号传导，药理AKT抑制剂LY294002抑制15-酮PGE2诱导的HO-1表达。15-酮PGE2产生活性氧，该活性氧被一般的抗氧化剂N-乙酰基-1-半胱氨酸抑制。N-乙酰基-1-半胱氨酸处理减弱了15-酮基PGE2诱导的GSK3β磷酸化，Nrf2的转录活性以及随后的HO-1表达。然而，缺少α，β-不饱和羰基部分的13,14-二氢-15-酮PGE2不能诱导细胞内产生活性氧，HO-1表达和Nrf2的核易位。