Abstract
Epithelial carcinomas of the ovary exhibit the highest mortality rate among gynecologic malignancies. Studies found that the metabolism of glycolipids or carbohydrates is associated with acquirement of anticancer drug-resistance by cancer cells. This study was to characterize possible involvement of Lewis Y (LeY) antigen in the drug-resistance of cancer cells. We transfected the α1,2-fucosyltransferase gene into human ovarian carcinoma-derived RMG-1 cells and established RMG-1-hFUT cells with enhanced expression of LeY. We determined the effects of docetaxel on the survival of cells by MTT assaying and observed the apoptosis of cells in the presence of docetaxel by flow cytometric analysis and by transmission electron microscopy. Plasma membranes and intracellular granules in RMG-1-hFUT cells were stained with anti-LeY antibody, the intensity of the staining was higher than that in control cells. The RMG-1-hFUT cells exhibited higher resistance to docetaxel than the control cells with regard to the docetaxel concentration and time course. After treatment with 10 μg/mL docetaxel for 72 h, the control cells, but not RMG-1-hFUT, contained abundant positively stained cell debris due to disintegration of the cytoskeleton. On transmission electron microscopy, although the control cells treated with docetaxel as above showed the following morphology, i.e., absence of villi, cells shrunken in size, pyknosis, agglutinated chromatin and cell buds containing nuclei in the process of apoptosis, the RMG-1-hFUT cells showed only agglutinated chromatin and vacuoles in the cytoplasm. In summary, cells with enhanced expression of LeY were shown to acquire docetaxel-resistance, indicating the possible involvement of glycoconjugates in the drug-resistance.
Highlights
Epithelial carcinomas of the ovary exhibit the highest mortality rate among gynecologic malignancies, that is, a 5-year survival rate in patients treated with cytoreductive surgery, and combined with chemotherapy only 30–40%
On immunocytochemical staining with anti-Lewis Y (LeY) antibody, RMG-1-hFUT cells established by transfection with the hFUT gene were found to express LeY antigen at a significantly higher level than the original RMG-1 cells and the RMG-1(-) cells transfected with the vector alone, and the
The relative survival rates of RMG-1, RMG-1(-) and RMG-1-hFUT cells cultured in the presence of docetaxel to those cultured without docetaxel were compared as functions of the docetaxel concentration and time course
Summary
Epithelial carcinomas of the ovary exhibit the highest mortality rate among gynecologic malignancies, that is, a 5-year survival rate in patients treated with cytoreductive surgery, and combined with chemotherapy only 30–40%. The resistance associated with glucosylation of ceramides is related to the removal of virulent ceramides, which are generated from sphingomyelin on activation of sphingomyelinase in the anticancer drug-induced apoptotic pathway [3,4]. Enhanced expression of LacCer and Gb3Cer with 2-hydroxy fatty acids and longer carbohydrate chains, together with that of transporters, was characteristically observed in paclitaxel- and cisplatin-resistant ovarian carcinoma-derived cells [5], and GM3 and Leb were found in paclitaxel-resistant cells [6], indicating that the metabolism of glycolipids or carbohydrates is associated with acquirement of anticancer drug-resistance by cancer cells. We previously demonstrated that transfection of the α1,2-fucosyltransferase gene into ovarian carcinoma-derived RMG-1 cells resulted in an increased amount of LeY antigen and enhanced anticancer drug resistance against 5-fluorouracil (5-FU) and carboplatin [7,8]. Lewis-related carbohydrate-structures were reported to be transformation-related antigens, that is, sialyl Lea for the metastatic potential [9,10], and Leb, LeY and
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