Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Abstract

Galactosylcerebroside is known to be overexpressed upon the cellular surface of a variety of cancers. In squamous cell carcinomas of the head and neck, one explanation for galactosylcerebroside accumulation has been identified as a transcriptional repression of the galactocerebrosidase gene. Galactocerebrosidase is the enzyme responsible for degrading galactosylcerebroside to ceramide. Ceramide is an important apoptosis activator, whereas galactosylcerebroside functions as an inhibitor. A shift of the ceramide metabolism balance in favor of glycosylated forms has been identified as a mechanism of drug resistance for several antineoplastic agents. Our review elaborates on possible explanations for galactocerebrosidase suppression and on other explanations for increased glycosphingolipid concentration within cancer cell membranes. Furthermore, conjecturable influences of a repressed galactocerebrosidase expression on tumor biology are to be explained. The inhibiting transcription factors YY1 and AP2 have been identified as potential galactocerebrosidase gene suppressors. The resulting accumulation of galactosylcerebroside promotes a reduction of cellular adhesion and inhibits apoptosis, leading to increased cellular growth, migration and prolonged cell survival contributing to carcinogenesis. ' 2005 Wiley-Liss, Inc.

Ceramide galactosyltransferase (UGT8) as a molecular marker of canine mammary tumor malignancy

“…Reaction intensities with rabbit polyclonal antibodies for UGT8 were calculated on the basis of the semiquantitative IRS scale of Remmele and Stegner (1987) The question remains as to the biological meaning of increased expression of UGT8. This enzyme is involved in the biosynthesis of GalCer, and it is possible that in human cancer, including breast cancer, an accumulation of this glycosphingolipid in tumor cells inhibits apoptosis, which facilitates metastatic cells to survive in the hostile micro-environment of the target organ [15,19]. Breast tumors and canine mammary neoplasia have many features in common.…”

Gene Expression Profiles Classify Human Osteosarcoma Xenografts According to Sensitivity to Doxorubicin, Cisplatin, and Ifosfamide

“…Further, two proapoptotic genes, GALC and PHLDA1, were strongly downregulated. GALC causes cellular accumulation of ceramide, which is an important second messenger of apoptosis (31), whereas downregulation of PHLDA1 contribute to apoptotic resistance in malignant melanoma (32). Interesting genes that overlapped with the profile for doxorubicin include HSP70 as well as DPP7, which has been described as an important regulator of apoptotic threshold in resting lymphocytes (33).…”

Galactosylceramide Affects Tumorigenic and Metastatic Properties of Breast Cancer Cells as an Anti-Apoptotic Molecule

“…In contrast, little attention has been paid to an alternative ceramide glycosylation pathway by the formation of GalCer. Interestingly, few years ago, it was proposed, however without any experimental evidence, that accumulation of GalCer in tumor cells could inhibit apoptosis which facilitates metastatic cells to survive in the hostile microenvironment of the target organ [30]. It was also documented that the tumor microenvironment by itself is the source of numerous cell stresses, such as hypoxia, acidosis, hyperglycemia, hyperosmotic pressure, high cell density, and free radicals which affect cancer cells [31].…”