Vendredi 9 décembre 2011 à 11 h 00
à l’invitation de Claudine Kieda
Séminaire Fédération FR2708
« The role of ceramide galactosylceramide (UGT8), new molecular marker of malignancy, in cancer progression »
Professeur Maciej Ugorski
Department of Histology and Embryology
T. Chałubińskiego 6a
The UDP-galactose:ceramide galactosyltransferase (UGT8) is the enzyme responsible for the synthesis of galactosylceramide (GalCer) which is known mostly as the constituent of myelin. Recently, we have shown that increased level of UGT8 in breast cancerous tissue is associated with progression to a more malignant phenotype, however very little is known about the possible functions of UGT8 and GalCer in tumor cells. On the basis of the existing data, it was proposed that accumulation of GalCer in tumor cells inhibits apoptosis, which facilitated metastatic cells to survive in the hostile microenvironment of the target organ. Therefore, to verify this hypothesis and study the role of this glycosphingolipid in breast cancer progression, we have used MCF7 cells overexpressing UGT8 and GalCer after transfection with UGT8 mRNA and MDA-MB-231 cells with highly decreased expression of UGT8 and GalCer after stable expression of shRNA directed against UGT8 mRNA. It was found that accumulation of GalCer in MCF7 cells increased their resistance to apoptosis induced by N-(4-hydroxyphenyl)retinamide (4-HPR). In the case of MDA-MB-231 cells, the down-regulation of GalCer resulted in increase sensitivity of breast cancer cells to doxorubicin-induced apoptosis. To further reveal the role of UGT8 and GalCer in breast cancer progression, the tumorigenicity and metastatic potential of parental MDA-MB-231 cells and GalCer-negative MDA-MB-231 cells was studied in vivo in athymic nu/nu mice. It was found that subcutaneous transplantation of tumor cells with no expression of GalCer, resulted in the formation of tumors with highly reduced volumes in comparison with mice inoculated with parental MDA-MB-231 cells. GalCer-negative breast cancer MDA-MD-231 cells were also characterized by markedly decreased ability to form metastases. When these cells were transplanted intracardiacaly, the average time of metastasis occurrence was markedly longer (14 weeks) in comparison with appearance of metastases after implantation of the parental MDA-MB-231 cells (6 weeks).
In conclusion, our data support the thesis on the importance of UGT8 and GalCer in the drug-induced apoptosis and the development of lung metastases by breast cancer cells.