PI3K/Akt signaling regulates p27(kip1) expression via Skp2 in PC3 and DU145 prostate cancer cells, but is not a major factor in p27(kip1) regulation in LNCaP and PC346 cells.
BACKGROUND
We compared the involvement of PI3K/PTEN/Akt signaling in the regulation of the cell-cycle regulator p27(kip1) and investigated the mechanism of PI3K/PTEN/Akt modulation of p27(kip1) in the prostate cancer cell lines LNCaP, PC346, PC3, and DU145.


METHODS
PI3K/PTEN/Akt signaling was manipulated by wortmannin or specific siRNA. The effects on PI3K/Akt downstream effectors and p27(kip1) expression were monitored on RNA and protein levels.


RESULTS
PI3K/Akt inhibition in LNCaP and PC346 cells hardly affected p27(kip1) expression. As shown in LNCaP cells, p27(kip1) expression inversely correlated with Skp2 expression, but Skp2 was not regulated by Akt. Blocking PI3K/Akt signaling in PC3 cells resulted in decreased Skp2 protein expression and increased p27(kip1). Downregulation of PTEN in DU145 cells also showed PTEN/Akt-dependent regulation of Skp2 and p27(kip1).


CONCLUSIONS
In PC3 and DU145 cells, Skp2 is the main determinant in the PI3K/Akt-dependent regulation of p27(kip1). In LNCaP and PC346 cells, PI3K/Akt signaling is not a major factor in p27(kip1) regulation.
van Duijn
Petra W
PW
Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Trapman
Jan
J
D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human