title: Galactosylceramide affects tumorigenic and metastatic properties of breast cancer cells as an anti-apoptotic molecule.
abstract: It was recently proposed that UDP-galactose:ceramide galactosyltransferase (UGT8), enzyme responsible for synthesis of galactosylceramide (GalCer), is a significant index of tumor aggressiveness and a potential marker for the prognostic evaluation of lung metastases in breast cancer. To further reveal the role of UGT8 and GalCer in breast cancer progression, tumorigenicity and metastatic potential of control MDA-MB-231 cells (MDA/LUC) and MDA-MB-231 cells (MDA/LUC-shUGT8) with highly decreased expression of UGT8 and GalCer after stable expression of shRNA directed against UGT8 mRNA was studied in vivo in athymic nu/nu mice. Control MDA/LUC cells formed tumors and metastatic colonies much more efficiently in comparison to MDA/LUC-shUGT8 cells with suppressed synthesis of GalCer after their, respectively, orthotopic and intracardiac transplantation. These findings indicate that UGT8 and GalCer have a profound effect on tumorigenic and metastatic properties of breast cancer cells. In accordance with this finding, immunohistochemical staining of tumor specimens revealed that high expression of UGT8 accompanied by accumulation of GalCer in MDA-MB-231 cells is associated with a much higher proliferative index and a lower number of apoptotic cells in comparison to the MDA/LUC-shUGT8 cells. In addition, it was found that expression of UGT8 in MDA-MB-231 cells increased their resistance to apoptosis induced by doxorubicin in vitro. Therefore, these data suggest that accumulation of GalCer in tumor cells inhibits apoptosis, which would facilitates metastatic cells to survive in the hostile microenvironment of tumor in target organ.
authors.affiliation: Laboratory of Glycobiology and Cell Interactions, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland ; Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, Wroclaw, Poland.
authors.forename: Tomasz B
authors.initials: TB
authors.lastname: Owczarek
authors.affiliation: Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, Wroclaw, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Suchanski
authors.affiliation: Department of Histology and Embryology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pula
authors.affiliation: Laboratory of Glycobiology and Cell Interactions, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Alicja M
authors.initials: AM
authors.lastname: Kmiecik
authors.affiliation: Laboratory of Glycobiology and Cell Interactions, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Chadalski
authors.affiliation: Department of Histology and Embryology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Jethon
authors.affiliation: Department of Histology and Embryology, Wroclaw Medical University, Wroclaw, Poland ; Department of Physiotherapy, Wroclaw University School of Physical Education, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Dziegiel
authors.affiliation: Laboratory of Glycobiology and Cell Interactions, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland ; Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, Wroclaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Ugorski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism*; D051147:Ganglioside Galactosyltransferase / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000556:secondary; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D005699:Galactosylceramides; D034741:RNA, Small Interfering; D004317:Doxorubicin; C511214:Ugt8a protein, mouse; D051147:Ganglioside Galactosyltransferase