title: Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells.
abstract: AKT isoforms are expressed in prostate cancer and their expression and localization have different associations with clinical characteristics. However, the distinct roles of the AKT isoforms in prostate cancer cells are largely unknown. In the present study, we demonstrate distinct roles for AKT1 and AKT2 in cell growth and migration. Ablation of AKT1 and AKT2 decreased the proliferation of the androgen-independent cell line PC-3, although by different mechanisms. AKT1 ablation induced loss of cell adhesion and subsequent apoptosis. AKT2 (but not AKT1) ablation promoted cell cycle arrest at G0/G1, associated with downregulation of cyclin D, CDK6 and CDK2, and upregulation and cytoplasmic-to-nuclear redistribution of p27. The increase of p27 protein levels was due to more gene transcription and an increase in protein stability. The increased stability of p27 was induced by delocalisation of Skp2 and a lower level of p27 phosphorylation at Thr187. AKT1 and AKT2 ablation inhibited and stimulated PC-3 cell migration, respectively. An AKT isoform-specific function could be associated with its subcellular localization. We found that AKT1 and AKT2 were mainly localised in the cytoplasm and nucleus, respectively. In androgen-sensitive cell line LNCaP, the ablation of AKT1 or AKT2 caused apoptosis but in androgen-independent LNCaP sublines, the effect of AKT1 ablation was lower; whereas no changes were observed after AKT2 ablation. Taken together, our data show that AKT1 and AKT2 have non-redundant roles in the regulation of PC-3 cell proliferation and migration. These could be explained by their subcellular localization and/or the specific regulation of downstream effectors. Furthermore, contribution of AKT isoforms to the progression of prostate cancer may change from an androgen-sensitive to a hormone-refractory stage. These findings may help design new targeted strategies for inhibiting AKT isoforms in prostate cancer.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Cariaga-Martinez
authors.forename: Pilar
authors.initials: P
authors.lastname: López-Ruiz
authors.forename: M Paz
authors.initials: MP
authors.lastname: Nombela-Blanco
authors.forename: Omar
authors.initials: O
authors.lastname: Motiño
authors.forename: Ana
authors.initials: A
authors.lastname: González-Corpas
authors.forename: Javier
authors.initials: J
authors.lastname: Rodriguez-Ubreva
authors.forename: María V T
authors.initials: MV
authors.lastname: Lobo
authors.forename: M Alicia
authors.initials: MA
authors.lastname: Cortés
authors.forename: Begoña
authors.initials: B
authors.lastname: Colás
mesh_terms: D023102:Anoikis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D008297:Male; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt