Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens.
OBJECTIVE
Sphingosine kinase-1 (SphK1) was shown in preclinical models and non-genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features.


METHODS
Transverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray.


RESULTS
A significant 2-fold increase in SphK1 enzymatic activity(11.1 ± 8.4 versus 5.9 ± 3.2 (P<0.04)) was observed in cancer. The upper quartile of SphK1 activity was associated with higher PSA (16.7 versus 6.4 ng/ml, P = 0.04), higher tumor volumes (20.7 versus 9.8, P = 0.002), higher rates of positive margins (85.7% versus 28.6%, P = 0.01) and surgical failure (71.4% versus 9.5%, P = 0.003) than the lower three quartiles. Odds ratios (OR) for treatment failure showed a strong relationship with SphK1 activity (OR: 23.7, P = 0.001), positive resection margins (OR: 15.0, P = 0.007) and Gleason sum (≥4+3, OR: 8.0, P = 0.003). Tissue microarrays showed discrete epithelial expression that varied with Gleason sum with significant relationship between SphK1 expression and higher Gleason sum.


CONCLUSIONS
In complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment.
Inserm, U466, Toulouse F-31000, France. malavaud.b@chu-toulouse.fr
Bernard
B
Malavaud
Dimitri
D
Pchejetski
Catherine
C
Mazerolles
Geisilène Russano
GR
de Paiva
Cyril
C
Calvet
Nicolas
N
Doumerc
Stuart
S
Pitson
Pascal
P
Rischmann
Olivier
O
Cuvillier
D000368:Aged; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D000099157:Sphingosine Kinase
D009363:Neoplasm Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase