Nejvíce citovaný článek - PubMed ID 29274292
Butyrate and docosahexaenoic acid interact in alterations of specific lipid classes in differentiating colon cancer cells
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.
- Klíčová slova
- AhR, Akt pathway, colon cancer cells, fatty acid synthesis, metabolism, proliferation,
- Publikační typ
- časopisecké články MeSH
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-dependent transcription factor that plays a role in various processes including differentiation of several cell types. We investigated the role of PPARα in the differentiation of intestinal cells using HT-29 and Caco2 cell lines as a model as well as human normal colon and colorectal carcinoma tissues. We detected a significant increase in PPARα expression in differentiated HT-29 cells as well as in normal surface colon epithelium where differentiated cells are localised. Thus, it seems that PPARα may play a role in differentiation of intestinal cells. Interestingly, we found that both PPARα activators (fenofibrate and WY-14643) as well as its inhibitor (GW6471) regulated proliferation and differentiation of HT-29 cells in vitro in the same way. Both compounds led to a decrease in proliferation accompanied by a significant increase in expression of villin, intestinal alkaline phosphatase (differentiation markers). Moreover, the same trend in villin expression was observed in Caco2 cells. Furthermore, villin expression was independent of subcellular localisation of PPARα. In addition, we found similar levels of PPARα expression in colorectal carcinomas in comparison to adjacent normal epithelium. All these findings support the hypothesis that differentiation of intestinal epithelium is PPARα-independent.
- Klíčová slova
- cell differentiation, cell proliferation, colorectal carcinoma, peroxisome-proliferator activated receptor,
- Publikační typ
- časopisecké články 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.
- Klíčová slova
- EpCAM, colorectal carcinoma, desaturation, epithelial cells, fatty acid synthesis, lipidomics, lysophospholipids, phospholipids,
- 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
- Názvy látek
- desaturasy mastných kyselin MeSH
- elongasy mastných kyselin MeSH
- ELOVL5 protein, human MeSH Prohlížeč
- FADS2 protein, human MeSH Prohlížeč
- fosfolipidy MeSH
- mastné kyseliny MeSH
- stearyl-CoA-desaturasa MeSH
- syntázy mastných kyselin MeSH
The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.
- Klíčová slova
- colon cancer (CRC) sphingolipidomics, colon cancer cells, colorectal cancer, glycosphingolipid, lactosylceramide, sphingolipid, sphingosine-1-phosphate,
- MeSH
- alkalická ceramidasa genetika metabolismus MeSH
- ceramidy metabolismus MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem genetika metabolismus MeSH
- kyselá ceramidasa genetika metabolismus MeSH
- laktosylceramidy metabolismus MeSH
- lidé MeSH
- lysofosfolipidy metabolismus MeSH
- metabolismus lipidů genetika MeSH
- modely nemocí na zvířatech MeSH
- nádorové buňky kultivované MeSH
- nádory tračníku enzymologie genetika patologie MeSH
- neutrální ceramidasa genetika metabolismus MeSH
- protoonkogenní proteiny c-akt genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sfingolipidy metabolismus MeSH
- sfingosin-N-acyltransferasa genetika metabolismus MeSH
- sfingosin analogy a deriváty metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- ACER2 protein, human MeSH Prohlížeč
- alkalická ceramidasa MeSH
- ASAH1 protein, human MeSH Prohlížeč
- ASAH2 protein, human MeSH Prohlížeč
- ceramide 1-phosphate MeSH Prohlížeč
- ceramidy MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem MeSH
- kyselá ceramidasa MeSH
- laktosylceramidy MeSH
- lysofosfolipidy MeSH
- neutrální ceramidasa MeSH
- protoonkogenní proteiny c-akt MeSH
- sfingolipidy MeSH
- sfingosin-N-acyltransferasa MeSH
- sfingosin MeSH
- sphingosine 1-phosphate MeSH Prohlížeč
- sphingosine kinase MeSH Prohlížeč