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.
Highlights
In 1874 Thudichum isolated from bovine brain the lipid fraction that was highly enriched in galactosylceramide [1], for which the final structure was established in 1952 by Carter and Greenwood [2] and its enzymatic synthesis was described by Morrel and Radin in 1969 [3]
GalCer inhibits tumor growth It was recently proposed that accumulation of GalCer in breast cancer cells inhibits apoptosis, which facilitates metastatic cells to survive in the hostile microenvironment of the target organ [14,30]
Such cells, named MDA/LUC-shUGT8, were characterized by highly decreased levels of UGT8 mRNA (Fig. 1A) and highly decreased binding of anti-UGT8 antibodies to cell lysates in comparison to control MDA/LUC cells obtained after transduction of MDA-MB-231 cells with pLVTHM/LUC vector (Fig. 1B)
Summary
In 1874 Thudichum isolated from bovine brain the lipid fraction that was highly enriched in galactosylceramide ( cerebroside) [1], for which the final structure was established in 1952 by Carter and Greenwood [2] and its enzymatic synthesis was described by Morrel and Radin in 1969 [3]. GalCer was primarily seen to be one of the major myelin stabilizing components [4] This glycolipid, in addition to oligodendrocytes and Schwann cells, is highly expressed in kidney and testis [5,6]. GalCer is synthesized by highly specific, reticulum-localized, glycosyltransferase UDP-ceramide:galactose galactosyltransferase (UGT8, EC 2.4.1.47) [9]. This enzyme is up-regulated in ERnegative breast cancer [10,11] and ovarian cancer as shown by microarray studies [12]. UGT8 was listed as one of six genes predicting breast cancer lung metastases [13]. We analyzed the presence of UGT8 and GalCer in breast cancer cell lines and found that cells with ‘‘luminal epithelial-like’’ phenotype did not express or weakly expressed UGT8 and GalCer, in contrast to malignant, ‘‘mesenchymal-like’’ cells forming metastases in nude mice [14]
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