Dataset Information

15d-PGJ2 inhibits NF-?B and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism.

ABSTRACT: Activation of peroxisome proliferator-activated receptor ? (PPAR?) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and overexpressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPAR?. In this study, we investigated the effects of induction of HO-1 by PPAR? on TPAinduced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-?B /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPAR? ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP- 9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPAR?/HO-1 signaling- pathway inhibition may be beneficial for prevention and treatment of breast cancer. [BMB Reports 2020; 53(4): 212-217].

PROVIDER: S-EPMC7196191 | BioStudies |

REPOSITORIES: biostudies

ACCESS DATA

Similar Datasets

Project description:HO-1 (haem oxygenase 1) is an essential antioxidant enzyme in the cell that exerts its effects through removal of pro-oxidant haem groups and the formation of antioxidant molecules and carbon monoxide. The electrophilic cyclopentenone 15d-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2) induces the expression of HO-1 protein through the covalent modification of protein thiols. It has been shown that specific thiol residues of the redox-sensor Keap1 (Kelch-like ECH-associated protein 1) are modified by 15d-PGJ2, leading to activation of the transcription factor Nrf-2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) and up-regulation of genes under control of the electrophile-response element, including HO-1. However, 15d-PGJ2 has also been shown to modify other proteins which comprise the electrophile-responsive proteome. Since 15d-PGJ2 has been shown to localize to the mitochondria in endothelial cells, we hypothesized that mitochondrial protein modification may also be important in Keap1/Nrf-2 signal transduction, leading to HO-1 up-regulation. In order to determine the role of mitochondrial protein thiol modification in HO-1 induction, we used the mitochondrial-targeted thiol-reactive compound IBTP [(4-iodobutyl)triphenylphosphonium]. IBTP had no effect on basal HO-1 levels, but effectively blocked HO-1 induction by a variety of reagents including haemin, iodoacetamide and 15d-PGJ2. Mechanistically, IBTP did not prevent the covalent modification of Keap1 by 15d-PGJ2. However, IBTP prevented the 15d-PGJ2-dependent increases in HO-1 mRNA and protein. Furthermore, IBTP prevented the nuclear accumulation of Nrf-2, suggesting cross-talk between mitochondria and antioxidant-response signal transduction. This effect was independent of reactive oxygen species formation or mitochondrial membrane potential. In addition, IBTP significantly enhanced the toxicity of high concentrations of 15d-PGJ2, suggesting that loss of mitochondrial control of HO-1 leads to increased susceptibility to electrophilic stress in endothelial cells. The implications for these studies in understanding the balance between cytoprotection and cytotoxicity in the context of diseases such as atherosclerosis is discussed.

Project description:Background:Abnormal upregulation of prostaglandin E2 (PGE2) is considered to be a key oncogenic event in the development and progression of inflammation-associated human colon cancer. It has been reported that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme catabolizing PGE2, is ubiquitously downregulated in human colon cancer. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ ligand, has been shown to have anticarcinogenic activities. In this study, we investigate the effect of 15d-PGJ2 on expression of 15-PGDH in human colon cancer HCT116 cells. Methods:HCT116 cells were treated with 15d-PGJ2 analysis. The expression of 15-PGDH in the treated cells was measured by Western blot analysis and RT-PCR. In addition, the cells were subjected to a 15-PGDH activity assay. To determine which transcription factor(s) and signaling pathway(s) are involved in 15d-PGJ2-induced 15-PGDH expression, we performed a cDNA microarray analysis of 15d-PGJ2-treated cells. The DNA binding activity of AP-1 was measured by an electrophoretic mobility shift assay. To determine whether the AP-1 plays an important role in the 15d-PGJ2-induced 15-PGDH expression, the cells were transfected with siRNA of c-Jun, a major subunit of AP-1. To elucidate the upstream signaling pathways involved in AP-1 activation by 15d-PGJ2, we examined its effect on phosphorylation of Akt by Western blot analysis in the presence or absence of kinase inhibitor. Results:15d-PGJ2 (10 μM) significantly upregulated 15-PGDH expression at the mRNA and protein levels in HCT-116 cells. 15-PGDH activity was also elevated by 15d-PGJ2. We observed that genes encoding C/EBP delta, FOS-like antigen 1, c-Jun, and heme oxygenase-1 (HO-1) were most highly induced in the HCT116 cells following 15d-PGJ2 treatment. 15d-PGJ2 increased the DNA binding activity of AP-1. Moreover, transfection with specific siRNA against c-Jun significantly reduced 15-PGDH expression induced by 15d-PGJ2. 15d-PGJ2 activates Akt and a pharmacological inhibitor of Akt, LY294002, abrogated 15d-PGJ2-induced 15-PGDH expression. We also observed that an inhibitor of HO-1, zinc protoporphyrin IX, also abrogated upregulation of 15-PGDH and down-regulation of cyclooxygenase-2 expression induced by 15d-PGJ2. Conclusions:These finding suggest that 15d-PGJ2 upregulates the expression of 15-PGDH through AP-1 activation in colon cancer HCT116 cells.

Dataset Information

15d-PGJ2 inhibits NF-?B and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure