A comprehensive analysis of transcript signatures of the phosphatidylinositol-3 kinase/protein kinase B signal-transduction pathway in prostate cancer.
OBJECTIVE
To assess the gene activities of various important members of the phosphatidylinositol 3 kinase (PIK3)/protein kinase B (PKB/Akt) pathway (involved in the promotion and regulation of cellular metabolism, proliferation and apoptosis) for alterations in prostate carcinoma.


METHODS
Using quantitative real-time reverse-transcription polymerase chain reaction, we analysed the transcript levels of 12 genes involved in the PIK3/PKB pathway in microdissected tumour tissues from 20 patients with varying stages of prostate cancer, assessing differences from adjacent normal tissues and from a pool of prostate tissues from healthy controls.


RESULTS
In cancer samples with a high Gleason grade, the PIK3/PKB pathway was principally affected by marked decreases in expression over almost all the investigated stages of the pathway. These changes were in effectors of the pathway, especially PIK3 p85 alpha (PIK3R1) and integrin-linked kinase, and the pathway target fork-head box protein (FOXO)-1A, while the transcript quantities of regulators, e.g. phosphatase/tensin homologue (PTEN), were decreased in a smaller proportion of the patients. Transcript amounts of FOXO-1A and FOXO-3A were significantly higher in normal tumour-adjacent tissues than in the healthy controls.


CONCLUSIONS
Down-regulation of the PIK3/PKB pathway by repression of involved effector and regulator genes at all stages of the molecular pathway could represent a marker for the formation of highly de-differentiated prostate cancers from low-grade tumour foci. Also, parts of the pathway are deviant in normal tumour-adjacent tissue; this might represent a reaction to neighbouring tumours or be a sign of pre-cancerous biological alterations.
Hellwinkel
Olaf J C
OJ
Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany. hellwinkel@uke.uni-hamburg.de
Rogmann
Jan-Peer
JP
Asong
Legrehndem E
LE
Luebke
Andreas M
AM
Eichelberg
Christian
C
Ahyai
Sascha
S
Isbarn
Hendrik
H
Graefen
Markus
M
Huland
Hartwig
H
Schlomm
Thorsten
T
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt