Analysis of complex protein kinase B signalling pathways in human prostate cancer samples

To provide a rational basis for targeted treatment approaches in prostate cancer deregulation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) system was analysed.

In all, 45 patients with primary localized prostate cancer that underwent radical prostatectomy were included in the present study. Upon scoring of the pathological grade, expression and phosphorylation levels of PKB/Akt and relevant downstream targets were determined in tissue specimens by immunohistochemistry using specific antibodies against PTEN, PKB/Akt, its downstream targets, and the respective phosphorylated proteins.

Most patients (>90%) had up-regulated expression and/or phosphorylation of PKB/Akt in the malignant tissue compared with the surrounding benign tissue, with a higher prevalence of increased phosphorylated PKB/Akt in patients with Gleason scores of > or =6 (100%) compared with those with Gleason scores of 4-5 (five of 13 patients), and in particular in patients with clinical progression. Up-regulated phosphorylation of PKB/Akt occurred either in association with loss or inactivation of PTEN or in a PTEN-independent manner. Enhanced phosphorylation levels of the PKB/Akt substrates glycogen synthase kinase 3, the mammalian target of rapamycin or the forkhead transcription factor like 1 (FKHRL1) were found in 29%, 42% and 40% of the tumours, respectively. Of these, only increased phosphorylated-FKHRL1 levels correlated with clinical progression. Interestingly, 80% of patients had a notable overexpression but not phosphorylation of the eucaryotic initiation factor 4E binding protein.

Deregulation of p-PKB/Akt is common in localized prostate cancer and has a putative value as predictive marker for disease progression and as therapeutic target. However, as a consequence of the substantial heterogeneity in the expression and phosphorylation levels of relevant PKB/Akt effector pathways, for a rational use of specified inhibitors of the PI3K/PKB system a complex pattern testing of expression and activity of the respective target proteins for prediction of efficacy and prognosis seems mandatory.