title: Silencing p110β prevents rapid depletion of nuclear pAkt.
abstract: The p110β subunit in the class IA PI3K family may act as an oncogene and is critical for prostate tumor development in PTEN knockout mice. We tested the possible involvement of p110β in a recently described rapid depletion of phosphorylated Akt (pAkt) in the nucleus. Previous work showed that this down-regulation is induced by extracellular ATP or by statins and is mediated by the purinergic receptor P2X7. Here, we used p110β knock out mouse embryonic fibroblasts (MEFs) and siRNA-treated cancer cells. We found that p110β is essential for ATP- or statin-induced nuclear pAkt depletion in MEFs and in several cancer cell lines including prostate cancer cells. ATP, statin or the selective P2X7 agonist BzATP also inhibited cell growth, and this inhibition was not seen in p110β knock out cells. We also found that p110β was necessary for statin-induced changes in binding between FKBP51, pAkt and PTEN. Our data show that p110β is essential for the ATP- and statin-induced effects and support a role of nuclear pAkt in cancer development. They also provide support for a chemopreventive effect of statins mediated by depletion of nuclear pAkt.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Zhi-wei
authors.initials: ZW
authors.lastname: Ye
authors.forename: Aram
authors.initials: A
authors.lastname: Ghalali
authors.forename: Johan
authors.initials: J
authors.lastname: Högberg
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology*; D058534:Class I Phosphatidylinositol 3-Kinases; D005347:Fibroblasts / Q000201:enzymology; D020868:Gene Silencing; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000069059:Atorvastatin; D058534:Class I Phosphatidylinositol 3-Kinases; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C487757:Pten protein, mouse