Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells

• Published in: Pathology oncology research Vol. 25; no. 1; pp. 391 - 399
• Main Authors: Kakkassery, Vinodh, Skosyrski, S., Lüth, A., Kleuser, B., van der Giet, M., Tate, R., Reinhard, J., Faissner, A., Joachim, S. C., Kociok, N.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.01.2019; Springer Nature B.V
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer; Cancer Research; Cell lines; Cell Proliferation; Cell Survival; Ceramide; Chemoresistance; Chemotherapy; Drug Resistance, Neoplasm; Enzymes; Etoposide; Etoposide - pharmacology; Gene expression; Humans; Immunology; Lipid metabolism; Lysophospholipids - metabolism; Mass spectrometry; Mass spectroscopy; Oncology; Original Article; Pathology; Phosphates; Retina; Retinoblastoma; Retinoblastoma - drug therapy; Retinoblastoma - metabolism; Retinoblastoma - pathology; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine 1-phosphate; Statistical analysis; Tumor Cells, Cultured; Tumors; Variance analysis; Retinoblastoma; Chemotherapy resistance; Sphingosine-1-phosphate
• ISSN: 1219-4956; 1532-2807
• DOI: 10.1007/s12253-017-0360-x

Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test ( p  < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines ( p  < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR ( p  < 0.01), but not in WERI Rb1 ( p  > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism.