Resistance to the antiproliferative effect induced by a short-chain ceramide is associated with an increase of glucosylceramide synthase, P-glycoprotein, and multidrug-resistance gene-1 in cervical cancer cells

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 4; pp. 809 - 817
• Main Authors: Gutiérrez-Iglesias, Gisela, Hurtado, Yamilec, Palma-Lara, Icela, López-Marure, Rebeca
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2014; Springer; Springer Nature B.V
• Subjects: Antineoplastic agents; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Cancer Research; Cell Proliferation - drug effects; Cervical cancer; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Female genital diseases; Genes, MDR - physiology; Glucosyltransferases - metabolism; Glycosylation - drug effects; Gynecology. Andrology. Obstetrics; Humans; Lactosylceramides - metabolism; Medical sciences; Medicine; Medicine & Public Health; Morpholines - antagonists & inhibitors; Morpholines - metabolism; Multidrug Resistance-Associated Proteins; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Tumor Cells, Cultured; Tumors; Uterine Cervical Neoplasms - metabolism; Lactosylceramide; P-gp; Glucosylceramide synthase; Ceramide; Glycosylation; Glucosylceramide; Proliferation; Antineoplastic agent; Cell proliferation; Short chain; Glycosyltransferases; P Glycoprotein; Uterine cervix; Ceramide glucosyltransferase; Tumor cell; Enzyme; Transferases; Sphingolipid; Malignant tumor; Female genital diseases; Resistance; MDR-1 gene; Hexosyltransferases; Uterine cervix diseases; Cervical cancer; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2552-3

Purpose Ceramide is glycosylated to glucosylceramide or lactosylceramide, and this glycosylation is a novel multidrug-resistance (MDR) mechanism. In this work, a short-chain ceramide (C6), lactosylceramide (LacCer), and an inhibitor of ceramide glycosylation ( d -threo-1-phenyl-2-decanoylamino-3-1-propanol, PDMP) were evaluated on the proliferation of cervical cancer cells. The participation of glucosylceramide synthase (GCS), P-glycoprotein (P-gp), and multidrug-resistance gene-1 (MDR-1) in the resistance to the antiproliferative effect induced by C6 was also evaluated. Methods Cell proliferation was determined by crystal violet staining. GCS and MDR-1 mRNA expression was evaluated by real-time RT-PCR assay. GCS and P-gp protein expressions, as well as Rhodamine 123 uptake, which is a functional test for P-gp efflux activity, were determined by flow cytometry. Results C6 inhibited proliferation of CaLo and CasKi cells with an IC 50 of 2.5 μM; however, 50 % proliferation of ViBo cells was inhibited with 10 μM. LacCer increased the proliferation of all cells. When cells were treated with PDMP plus C6, no additional effect on antiproliferation induced by C6 was observed in CaLo and CasKi cells; however, proliferation diminished in comparison with C6 alone in ViBo cells. C6 increased GCS and MDR-1 expression in all cells, as well as P-gp expression in CasKi cells. Conclusions Cells that have more capacity to glycosylate ceramide and express a higher level of GCS, MDR-1, and P-gp, are more resistant to the antiproliferative effect induced by C6.