Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens
Introduction
Sphingosine 1-phosphate (S1P) has emerged as a critical lipid mediator that promotes tumour cell proliferation, survival, migration and angiogenesis (reviewed in 1, 2). It has been suggested that the balance between the intracellular levels of S1P and its metabolic precursors ceramide and sphingosine provides a rheostat mechanism that decides whether a cell undergoes apoptosis (via ceramide and sphingosine) or proliferates and survives by S1P.3 A decisive regulator of this sphingolipid switch is the sphingosine kinase-1 (SphK1), the enzyme whose role is to convert the death-promoting sphingolipid sphingosine into the growth-promoting S1P. While SphK1 activity can be stimulated by a wide array of growth factors (reviewed in 4), anticancer treatments cause its down-regulation,5, 6, 7, 8, 9, 10 and small molecule inhibitors of SphK1 can reduce tumor volume in animal models.11, 12, 13, 14, 15
Further supporting a role for SphK1 in promoting cancer, SphK1 has been found to act as an oncogene,16 and SphK1 mRNA levels have been found significantly higher in various tumour tissues such as those of breast, colon, lung, ovary, stomach, uterus, kidney, rectum and small intestine, than in normal tissues.11, 17 Bone marrow cells isolated from acute leukaemia and myelodysplastic syndrome patients also displayed a noticeable increase of SphK1 mRNA as compared to normal population.18 Interestingly, increased SphK1 mRNA is correlated to increasing clinical grade in non-Hodgkin lymphomas.19 More importantly, a correlation was found between the mRNA content of SphK1 with short survival in grade IV human astrocytoma,20 and oestrogen-receptor positive breast cancer patients.21 In non-small-cell lung carcinomas or pancreatic adenocarcinoma, strong immunopositive staining for SphK1 in cancerous lesions as compared with normal adjacent tissue17, 22 suggested that increased mRNA levels were generally reflected in increased protein expression. A significant correlation was noted between SphK1 expression and histopathological staging in astrocytomas, gastric and colon cancer, supporting the notion that SphK1 plays a role in progression of these diseases.23, 24, 25 In addition, a remarkable correlation was found between shorter overall survival times of patients and high SphK1 expression for astrocytomas and gastric cancer, suggesting that SphK1 could also be a prognostic marker.24, 25
Following lung cancer, prostate cancer has become the second leading cause of death by cancer in the United States. The American Cancer Society estimates are 192,000 new cases and 28,000 deaths in 2009.26 So far, the relevance of the sphingolipid rheostat governed by SphK1 with regard to prostate cancer progression/resistance has only been suggested in cell7, 8, 9, 27, 28 or pre-clinical animal models.9, 15
Herein, we report for the first time the location and variability of SphK1 expression in prostate tumours. We further relate the quantification of the SphK1 enzymatic activity in freshly retrieved specimens of individual tumours and corresponding normal tissues to clinical features.
Section snippets
Patients and specimens handling
Tissue samples of 30 prostate cancer cases were obtained after IRB approval (Clinical Trial 0305302 from the Hôpitaux de Toulouse) and informed consent from consecutive patients undergoing laparoscopic radical prostectomies performed for clinical T1c–T2c with at least two positive biopsies from 12/2003 to 7/2004. The clinical stage was assigned by the referring urologist according to the 2002 TNM classification.29 No patients received neoadjuvant treatment by radiation or hormonal manipulation.
Sphingosine kinase-1 activity
Thirty consecutive patients were enrolled. For two patients, no tumour was found in the mid-specimen section. Patients’ characteristics are presented in Table 1. Median age was 63.9 years [95% confidence interval (CI): 61.5–66.3], median preoperative serum total PSA level was 9.0 ng/ml (95% CI: 5.7–12.3). Median follow-up before biochemical relapse or adjuvant treatment or no evidence of recurrence was 30 months (range 1–56.2 months). As a whole, median sphingosine kinase-1 (SphK1) activity was 11.0
Discussion
Sphingolipids signalling has emerged as a key integrated system controlling a wide array of molecular functions involved in crucial steps of cancer natural history from promotion and progression to response to treatments (reviewed in 2). Across the complexities of sphingolipid biology, sphingosine kinase type 1 (SphK1) has the pivotal role of phosphorylating anti-apoptotic ceramide/sphingosine into sphingosine 1-phosphate (S1P) that can act intracellularly or through dedicated extracellular
Conclusion
The reported relationship between activity and prognostic factors such as PSA, tumour volume and positive resection margin supports a central role for SphK1 in the early stages of prostate cancer, complementing preclinical studies where it was shown to be a key regulator of response to local treatment and chemotherapy. We believe that SphK1 fully meets the main criteria required for the development of targeted therapy45 and supports promising perspectives in prostate cancer risk-assessment and
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), and the Hôpitaux de Toulouse.
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