"RO 0520" Dotaz Zobrazit nápovědu
The aryl hydrocarbon receptor (AhR) plays a wide range of physiological roles in cellular processes such as proliferation, migration or control of immune responses. Several studies have also indicated that AhR might contribute to the regulation of energy balance or cellular metabolism. We observed that the AhR is upregulated in tumor epithelial cells derived from colon cancer patients. Using wild-type and the corresponding AhR knockout (AhR KO) variants of human colon cancer cell lines HCT116 and HT-29, we analyzed possible role(s) of the AhR in cell proliferation and metabolism, with a focus on regulation of the synthesis of fatty acids (FAs). We observed a decreased proliferation rate in the AhR KO cells, which was accompanied with altered cell cycle progression, as well as a decreased ATP production. We also found reduced mRNA levels of key enzymes of the FA biosynthetic pathway in AhR KO colon cancer cells, in particular of stearoyl-CoA desaturase 1 (SCD1). The loss of AhR was also associated with reduced expression and/or activity of components of the PI3K/Akt pathway, which controls lipid metabolism, and other lipogenic transcriptional regulators, such as sterol regulatory element binding transcription factor 1 (SREBP1). Together, our data indicate that disruption of AhR activity in colon tumor cells may, likely in a cell-specific manner, limit their proliferation, which could be linked with a suppressive effect on their endogenous FA metabolism. More attention should be paid to potential mechanistic links between overexpressed AhR and colon tumor cell metabolism.
- Publikační typ
- časopisecké články MeSH
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.
Sex chromatin is a conspicuous body that occurs in polyploid nuclei of most lepidopteran females and consists of numerous copies of the W sex chromosome. It is also a cytogenetic tool used to rapidly assess the W chromosome presence in Lepidoptera. However, certain chromosomal features could disrupt the formation of sex chromatin and lead to the false conclusion that the W chromosome is absent in the respective species. Here we tested the sex chromatin presence in 50 species of Geometridae. In eight selected species with either missing, atypical, or normal sex chromatin patterns, we performed a detailed karyotype analysis by means of comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). The results showed a high diversity of W chromosomes and clarified the reasons for atypical sex chromatin, including the absence or poor differentiation of W, rearrangements leading to the neo-W emergence, possible association with the nucleolus, and the existence of multiple W chromosomes. In two species, we detected intraspecific variability in the sex chromatin status and sex chromosome constitution. We show that the sex chromatin is not a sufficient marker of the W chromosome presence, but it may be an excellent tool to pinpoint species with atypical sex chromosomes.
- MeSH
- druhová specificita MeSH
- hybridizace in situ fluorescenční MeSH
- karyotyp MeSH
- můry genetika MeSH
- pohlavní chromozomy genetika MeSH
- sexchromatin metabolismus MeSH
- srovnávací genomová hybridizace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.
- MeSH
- adenokarcinom enzymologie genetika metabolismus MeSH
- desaturasy mastných kyselin genetika metabolismus MeSH
- elongasy mastných kyselin genetika metabolismus MeSH
- epitelové buňky enzymologie metabolismus MeSH
- fosfolipidy metabolismus MeSH
- lidé MeSH
- lipidomika MeSH
- lipogeneze MeSH
- mastné kyseliny metabolismus MeSH
- metabolismus lipidů * MeSH
- nádory tračníku enzymologie genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- senioři MeSH
- stearyl-CoA-desaturasa genetika metabolismus MeSH
- syntázy mastných kyselin genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Polycyclic aromatic hydrocarbons (PAHs) represent a class of widely distributed environmental pollutants that have been primarily studied as genotoxic compounds. Their mutagenicity/genotoxicity largely depends on their oxidative metabolism leading to the production of dihydrodiol epoxide metabolites, as well as additional metabolites contributing to oxidative DNA damage, such as PAH quinones. However, both parental PAHs and their metabolites, including PAH quinones or hydroxylated PAHs, have been shown to produce various types of non-genotoxic effects. These include e.g., activation of the aryl hydrocarbon receptor and/or additional nuclear receptors, activation of membrane receptors, including tyrosine kinases and G-protein coupled receptors, or activation of intracellular signaling pathways, such as mitogen-activated protein kinases, Akt kinase and Ca2+-dependent signaling. These pathways may, together with the cellular DNA damage responses, modulate cell proliferation, cell survival or cell-to-cell communication, thus contributing to the known carcinogenic effects of PAHs. In the present review, we summarize some of the known non-genotoxic effects of PAHs, focusing primarily on those that have also been shown to be modulated by PAH metabolites. Despite the limitations of the available data, it seems evident that more attention should be paid to the discrimination between the potential non-genotoxic effects of parental PAHs and those of their metabolites. This may provide further insight into the mechanisms of toxicity of this large and diverse group of environmental pollutants.
- MeSH
- látky znečišťující životní prostředí farmakokinetika toxicita MeSH
- lidé MeSH
- metabolická aktivace MeSH
- mutageny farmakokinetika toxicita MeSH
- oxidační stres MeSH
- polycyklické aromatické uhlovodíky farmakokinetika toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
