Article
The role of sphingosine kinase isoforms and their receptors in growth of primary, secondary and recurrent glioblastoma
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Authors
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M. Kolodziej
- Neurochirurgische Klinik, Philipps-Universität Marburg
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N. Stiel
- Philipps-Universität Marburg
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K. Quint
- Institut für Theroretischen Chirurgie, Philipps-Universität Marburg
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M. Ocker
- Institut für Theroretischen Chirurgie, Philipps-Universität Marburg
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H. Strik
- Neurologische Klinik, Philipps-Universität Marburg
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L. Benes
- Neurochirurgische Klinik, Philipps-Universität Marburg
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C. Nimsky
- Neurochirurgische Klinik, Philipps-Universität Marburg
| Published: | April 28, 2011 |
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Outline
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Objective: Sphingosine 1-phosphate (S1P), a sphingolipid metabolite playing an important role in the regulation of cell survival, growth, migration and angiogenesis, acts both inside the cells and as an extracellular mediator through binding to five G protein-coupled receptors, S1P1-5. Sphingosine kinase 1 (SK1), the enzyme responsible for S1P production, is over-expressed in many solid tumors including gliomas. In one of the first studies, it was shown that the expression of SK1 had an effect on the survival times of glioma patients. However, the role of the enzymes SK-1 and -2 and of the receptors S1P1-5 has not been thoroughly investigated yet.
Methods: Following surgical resection or biopsy, a pathologist confirmed the diagnosis of glioblastoma multiforme. Cryopreservation of the tumor tissue was performed by conventional slow-freezing, followed by RNA isolation and cDNA conversion. The expression levels of SK 1 and 2 and their receptors 1-5 were investigated by quantitative real-time PCR and normalized against housekeeping genes.
Results: In the present study we investigated tumor-tissue of 55 patients, 34 with primary, 4 with secondary and 17 with recurrent glioblastoma. In three cases, specimens of primary and recurrent tumors from the each patient, and for two additional patients, specimens of the second recurrence were available. In primary tumors, expression levels of SK1 were higher compared to SK2, whereas the expression of SK1 increased in the recurrent tumors. The expression of the receptors S1PR2, S1PR3 and S1PR5 were down-regulated in the recurrent tumors independent of the therapy used (p<0.05). In recurrent tumors of patients receiving combined radiation and chemotherapy after surgery, SK1 was over-expressed and the receptors S1PR2 and S1PR3 were down-regulated (p<0.05). After singular therapy consisting of radiation or chemotherapy alone, the receptors S1PR3 and S1PR5 were down-regulated significantly (S1PR3: p<0.01, S1PR5: p<0.05).
Conclusions: The expression of the receptor S1PR3 is down-regulated in the combined therapy, while the down regulation of the receptor S1PR5 is typical for the singular therapy. The over-expression of SK1 signifies the increased malignancy of recurrent tumors. In addition to the standard chemotherapy regimen against GBM, a sphingosine kinase inhibitor and pharmacologic receptor modulation may be beneficial.
