Possible role of the aryl hydrocarbon receptor in modulation of sphingolipid and glycosphingolipid metabolism in colon cancer cell models

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F22%3AN0000128" target="_blank" >RIV/00027162:_____/22:N0000128 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Possible role of the aryl hydrocarbon receptor in modulation of sphingolipid and glycosphingolipid metabolism in colon cancer cell models

Popis výsledku v původním jazyce

BACKGROUND. The aryl hydrocarbon receptor (AhR) is ligand-activated transcription factor with many different physiological and pathophysiological functions, which has been found to be overexpressed in colon tumor tissue. AhR is involved in xenobiotics- and endogenous metabolism; however its role(s) in sphingolipid (SL) and glycosphingolipid (GSL) metabolism is poorly understood. RESULTS. In our work, we determined SL and GSL levels as well as the expression of the principle enzymes controlling SL/GSL metabolism in colon cancer epithelial cell models. We employed DLD-1, HT-29 and HCT-116 colon carcinoma cell lines, as well as their AhR KO counterparts, that were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR agonist. We observed both common and cell-specific changes in SL and GSL levels. In HT-29 cells, TCDD induced an accumulation of dihydroceramides, GM3 C16:0 and GD3 C24:1; AhR depletion led to induction of phosphorylated sphinganine, sphingosine and ceramide as well as to increase in glucosylceramide levels, while AhR KO caused specific increase in C24:1 SL/GSLs (including dihydroceramide, ceramide, ceramide-1-phosphate, sphingomyelin, glucosylceramide, galactosylceramide and lactosylceramide, as well as increased levels of Gb3, GM3 and GD3). The AhR KO in HCT-116 cells, led to suppression of dihydroceramides, dihydrosphingomyelin and to induction of ceramide-1-phosphate, sulfatide C16:0 and lactosylceramide C24:1. Finally, in DLD-1 cells, we identified 3 SL/GSL metabolism genes as candidate direct targets of the AhR (SPHK1, B3GALT4 and ST3GAL5). Interestingly, other SL/GSL metabolism genes in colin cancer cells were mostly regulated in a similar manner either by TCDD or by AhR knockout. This might be linked with AhR protein depletion elicited via its proteasomal degradation upon TCDD treatment. CONCLUSION. Present results indicate that constitutive AhR activity might be involved in the control of SL and GSL biosynthesis; however, the effect of AhR activation and/or inhibition were often cell-specific and may depend on further cell alternations occurring during colon tumorigenesis. The most consistent changes observed upon TCDD treatment included accumulation of dihydroceramides in both HT-29 and DLD-1 cells, as well as that of GM3 C16:0 and GD3 C24:1 in HT-29 cells. Since AhR may affect multiple SL metabolic pathways in colon epithelial cells, the deregulation of SL/GSL metabolism via AhR action should be studied in a more detail. [This study was supported by the Ministry of Health of the Czech Republic, grant no. NU21-03-00421].

Název v anglickém jazyce

Possible role of the aryl hydrocarbon receptor in modulation of sphingolipid and glycosphingolipid metabolism in colon cancer cell models

Popis výsledku anglicky

BACKGROUND. The aryl hydrocarbon receptor (AhR) is ligand-activated transcription factor with many different physiological and pathophysiological functions, which has been found to be overexpressed in colon tumor tissue. AhR is involved in xenobiotics- and endogenous metabolism; however its role(s) in sphingolipid (SL) and glycosphingolipid (GSL) metabolism is poorly understood. RESULTS. In our work, we determined SL and GSL levels as well as the expression of the principle enzymes controlling SL/GSL metabolism in colon cancer epithelial cell models. We employed DLD-1, HT-29 and HCT-116 colon carcinoma cell lines, as well as their AhR KO counterparts, that were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR agonist. We observed both common and cell-specific changes in SL and GSL levels. In HT-29 cells, TCDD induced an accumulation of dihydroceramides, GM3 C16:0 and GD3 C24:1; AhR depletion led to induction of phosphorylated sphinganine, sphingosine and ceramide as well as to increase in glucosylceramide levels, while AhR KO caused specific increase in C24:1 SL/GSLs (including dihydroceramide, ceramide, ceramide-1-phosphate, sphingomyelin, glucosylceramide, galactosylceramide and lactosylceramide, as well as increased levels of Gb3, GM3 and GD3). The AhR KO in HCT-116 cells, led to suppression of dihydroceramides, dihydrosphingomyelin and to induction of ceramide-1-phosphate, sulfatide C16:0 and lactosylceramide C24:1. Finally, in DLD-1 cells, we identified 3 SL/GSL metabolism genes as candidate direct targets of the AhR (SPHK1, B3GALT4 and ST3GAL5). Interestingly, other SL/GSL metabolism genes in colin cancer cells were mostly regulated in a similar manner either by TCDD or by AhR knockout. This might be linked with AhR protein depletion elicited via its proteasomal degradation upon TCDD treatment. CONCLUSION. Present results indicate that constitutive AhR activity might be involved in the control of SL and GSL biosynthesis; however, the effect of AhR activation and/or inhibition were often cell-specific and may depend on further cell alternations occurring during colon tumorigenesis. The most consistent changes observed upon TCDD treatment included accumulation of dihydroceramides in both HT-29 and DLD-1 cells, as well as that of GM3 C16:0 and GD3 C24:1 in HT-29 cells. Since AhR may affect multiple SL metabolic pathways in colon epithelial cells, the deregulation of SL/GSL metabolism via AhR action should be studied in a more detail. [This study was supported by the Ministry of Health of the Czech Republic, grant no. NU21-03-00421].

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/NU21-03-00421" target="_blank" >NU21-03-00421: Glykosfingolipidy a jejich metabolické dráhy jako potenciální biomarkery nádorů tlustého střeva</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů