Delineating the mechanism by which selenium deactivates Akt in prostate cancer cells.
The up-regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is prevalent in many cancers. This phenomenon makes PI3K and Akt fruitful targets for cancer therapy and/or prevention because they are mediators of cell survival signaling. Although the suppression of phospho-Akt by selenium has been reported previously, little information is available on whether selenium modulates primarily the PI3K-phosphoinositide-dependent kinase 1 (PDK1) side of Akt phosphorylation or the phosphatase side of Akt dephosphorylation. The present study was aimed at addressing these questions in PC-3 prostate cancer cells which are phosphatase and tensin homologue-null. Our results showed that selenium decreased Akt phosphorylation at Thr308 (by PDK1) and Ser473 (by an unidentified kinase); the Thr308 site was more sensitive to selenium inhibition than the Ser473 site. The protein levels of PI3K and phospho-PDK1 were not affected by selenium. However, the activity of PI3K was reduced by 30% in selenium-treated cells, thus discouraging the recruitment of PDK1 and Akt to the membrane due to low phosphatidylinositol-3,4,5-trisphosphate formation by PI3K. Consistent with the above interpretation, the membrane localization of PDK1 and Akt was significantly diminished as shown by Western blotting. In the presence of a calcium chelator or a specific inhibitor of calcineurin (a calcium-dependent phosphatase), the suppressive effect of selenium on phospho-Akt(Ser473) was greatly reduced. The finding suggests that selenium-mediated dephosphorylation of Akt via calcineurin is likely to be an additional mechanism in regulating the status of phospho-Akt.
Wu
Yue
Y
Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Zu
Ke
K
Warren
Mary Ann
MA
Wallace
Paul K
PK
Ip
Clement
C
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D006801:Humans; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000037:antagonists & inhibitors*; D012643:Selenium / Q000627:therapeutic use; D013912:Threonine / Q000378:metabolism
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents; D019703:Calcineurin; D002118:Calcium; D016566:Organoselenium Compounds; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012643:Selenium; D013912:Threonine; C060974:phosphatidylinositol 3,4,5-triphosphate; C008493:methylselenic acid; C578562:PDPK1 protein, human