15-Deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂), an endogenous ligand for PPARγ, has differential effects on cancer cell proliferation and survival depending on the dose and the type of cells. In the present study, we have investigated the effects of 15d-PGJ₂ on apoptosis of the Ha-ras transformed human breast epithelial (MCF10A-ras) cells. When MCF10A-ras cells were treated with 15d-PGJ₂ (10 μM) for 24 hours, they underwent apoptosis as evidenced by characteristic morphological features, an increased proportion of sub-G₀/G₁ cell population, a typical pattern of annexin V/propidium iodide staining, perturbation of mitochondrial transmembrane potential (Δψ_m), and cleavage of caspase-3 and its substrate PARP. A pan-caspase inhibitor, Z-Val-Ala-Asp (OCH₃)-fluoromethyl ketone attenuated cytotoxicity and proteolytic cleavage of caspase-3 induced by 15d-PGJ₂. The 15d-PGJ₂-induced apoptosis was accompanied by enhanced intracellular accumulation of reactive oxygen species (ROS), which was abolished by the antioxidant N-acetyl-L-cysteine (NAC). 15d-PGJ₂ inhibited the DNA binding activity of NF-κB which was associated with inhibition of expression and catalytic activity of IκB kinase β (IKKβ). 15d-PGJ₂-mediated inhibition of IKKβ and nuclear translocation of phospho-p65 was blocked by NAC treatment. 9,10-Dihydro-PGJ₂, a non-electrophilic analogue of 15d-PGJ₂, failed to produce ROS, to inhibit NF-κB DNA binding, and to induce apoptosis, suggesting that the electrophilic α,β-unsaturated carbonyl group of 15d-PGJ₂ is essential for its pro-apoptotic activity. 15d-PGJ₂-induced inactivation of IKKβ was also attributable to its covalent thiol modification at the cysteine 179 residue of IKKβ. Based on these findings, we propose that 15d-PGJ₂ inactivates IKKβ-ΝF-κB signaling through oxidative or covalent modification of IKKβ, thereby inducing apoptosis in Ha-ras transformed human breast epithelial cells.

2019-07-01·Biochemistry and Biophysics Reports

15-deoxy-Δ12, 14-prostaglandin J2 enhances anticancer activities independently of VHL status in renal cell carcinomas

Article

作者: Yamamoto, Yasuhiro ; Fujita, Tomonari ; Koma, Hiromi ; Yagami, Tatsurou

Renal cell carcinoma (RCC) is relatively resistant to chemotherapy and radiotherapy. Clear cell RCC (ccRCC) accounts for the majority of RCC, which have mutations or epigenetic silencing of the von Hippel-Lindau (VHL) gene. VHL-positive Caki-2 cells are killed by an endogenous anticancer substance, 15-deoxy-Δ^{12, 14}-prostaglandin J₂ (15d-PGJ₂). The MTT reduction assay reflecting mitochondrial succinate dehydrogenase activity was employed for assessment of cell viability. We confirmed anticancer activities of camptothecin (topoisomerase I inhibitor), etoposide (topoisomerase II inhibitor), doxorubicin (topoisomerase II inhibitor) in VHL-positive Caki-2 cells. Combination of topoisomerase inhibitors with 15d-PGJ₂ exhibited the synergistic effect in VHL-positive Caki-2 cells. However, 15d-PGJ₂ did not increase cytotoxicities of topoisomerase inhibitors on VHL-negative 786-O cells. In addition, the 15d-PGJ₂-enhanced antitumor activity of topoisomerase inhibitors was detected in neither VHL-positive nor VHL-negative RCC4 cells. Our finding indicated that 15d-PGJ₂ enhanced the antitumor activity of topoisomerase inhibitors independently of VHL.

2016-06-01·The Journal of Clinical Endocrinology & Metabolism2区 · 医学

Nrf2 Activation Inhibits Effects of Thrombin in Human Amnion Cells and Thrombin-Induced Preterm Birth in Mice

2区 · 医学

Article

作者: Mogami, Haruta ; Word, Ruth Ann ; Chigusa, Yoshitsugu ; Kishore, Annavarapu Hari

CONTEXTNrf2 is a key transcription factor that modulates cell defense mechanisms against endogenous and exogenous stress. Previously, we reported that thrombin increased matrix metalloproteinases and prostaglandin synthesis in human amnion mesenchymal cells.OBJECTIVEWe sought to determine whether activation of Nrf2 alters the effect of thrombin on prostaglandin synthesis, protease activation, and cytokine release in human amnion. Furthermore, we analyzed the effect of Nrf2 activation on thrombin-induced preterm labor in mice.DESIGNPrimary human amnion mesenchymal cells and pregnant mice were employed to investigate the effect of Nrf2 on thrombin-induced inflammation and preterm birth.SETTINGThis was a laboratory-based study using cells and mice.RESULTSAs expected, thrombin increased cyclooxygenase-2, IL-1β, IL-6, IL-8, and matrix metalloproteinase-1 in amnion mesenchymal cells. Preincubation with Nrf2 activators, diethyl maleate or 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), profoundly repressed thrombin-induced gene expression. In addition, Nrf2 activation inhibited thrombin-induced cyclooxygenase-2 protein levels and secretion of prostaglandin E2, IL-1β, IL-6, IL-8, TNFα, and granulocyte-macrophage colony-stimulating factor in the media. Whereas vehicle and 15d-PGJ2 did not alter gestational length, all pregnant mice treated with thrombin delivered preterm. 15d-PGJ2 delayed thrombin-induced preterm birth significantly.CONCLUSIONSThe results indicate that Nrf2 activation represents a key stress response in amnion mesenchyme cells and in pregnant mice to mitigate the adverse proinflammatory effects of thrombin on the fetal membranes. We suggest, therefore, that pharmacological activation of Nrf2 may prevent the increased risk of preterm premature rupture of the membranes associated with thrombin activation that accompanies subchorionic hemorrhage or bleeding during pregnancy.

100 项与 15d-PGJ2 相关的药物交易

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