Ceramide biosynthesis and metabolism in trophoblast syncytialization.
Sphingolipid mediators such as ceramide are pleiotropic regulators of cellular growth, differentiation and apoptosis. We investigated the role of ceramide biosynthesis, metabolism and actions in term human cytotrophoblasts syncytialized over 7 days in culture. Intracellular C16 ceramide levels increased modestly after 3 days in culture, then declined. Ceramidase was present at particularly high levels in syncytialized trophoblasts; inhibition of ceramidase reduced the degree of cell fusion. Exposure to short chain C8 ceramide or aSMase enhanced secretion of the differentiation marker hCG without affecting fusion or cell viability. In contrast, pharmacological inhibition of ceramidase reduced the extent of fusion. Inhibition of the ceramide-responsive JNK and PP2A pathways did not abolish the effects of ceramide, and JNK phosphorylation was unresponsive to ceramide; however, ceramide significantly inhibited phosphorylation of Akt. This study suggests that changes in ceramide biosynthesis and metabolism play a differential role in the biochemical and morphological features of trophoblast differentiation.
School of Women's and Infant's Health, Dentistry and Health Sciences, The University of Western Australia, Perth, Australia.
Ambika T
AT
Singh
Arunasalam
A
Dharmarajan
Irving L M H
IL
Aye
Jeffrey A
JA
Keelan
D000873:Anthracenes / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D002478:Cells, Cultured; D055572:Ceramidases / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D006063:Chorionic Gonadotropin / Q000378:metabolism; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D015726:Giant Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011714:Pyrans / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*
D000873:Anthracenes; D000943:Antigens, Differentiation; D002518:Ceramides; D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C491089:GCM1 protein, human; D009687:Nuclear Proteins; D011714:Pyrans; D013141:Spiro Compounds; D014157:Transcription Factors; C053079:tautomycin; C432165:pyrazolanthrone; D019319:Okadaic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase; D013108:Sphingomyelin Phosphodiesterase; C505530:CASP8 protein, human; D053181:Caspase 8; D055572:Ceramidases