Candidate tumor suppressor B-cell translocation gene 3 impedes neoplastic progression by suppression of AKT
Journal
Cell Death and Disease
Journal Volume
6
Journal Issue
1
Pages
e1584
Date Issued
2015
Author(s)
Cheng Y.-C.
Chen P.-H.
Chiang H.-Y.
Suen C.-S.
Hwang M.-J.
Lin T.-Y.
Yang H.-C.
Lai P.-L.
Shieh S.-Y.
Abstract
BTG3 (B-cell translocation gene 3) is a p53 target that also binds and inhibits E2f1. Although it connects two major growthregulatory pathways functionally and is downregulated in human cancers, whether and how BTG3 acts as a tumor suppressor remain largely uncharacterized. Here we present evidence that BTG3 binds and suppresses AKT, a kinase frequently deregulated in cancers. BTG3 ablation results in increased AKT activity that phosphorylates and inhibits glycogen synthase kinase 3β. Consequently, we also observed elevated β-catenin/T-cell factor activity, upregulation of mesenchymal markers, and enhanced cell migration. Consistent with these findings, BTG3 overexpression suppressed tumor growth in mouse xenografts, and was associated with diminished AKT phosphorylation and reduced β-catenin in tissue specimens. Significantly, a short BTG3-derived peptide was identified, which recapitulates these effects in vitro and in cells. Thus, our study provides mechanistic insights into a previously unreported AKT inhibitory pathway downstream of p53. The identification of an AKT inhibitory peptide also unveils a new avenue for cancer therapeutics development. ? 2015 Macmillan Publishers Limited All rights reserved.
SDGs
Other Subjects
B cell translocation gene 3 protein; beta catenin; glycogen synthase kinase 3beta; protein kinase B; protein p53; T cell factor protein; unclassified drug; beta catenin; BTG3 protein, human; glycogen synthase kinase 3; glycogen synthase kinase 3 beta; peptide; protein; protein binding; protein kinase B; protein serine threonine kinase; pyruvate dehydrogenase (acetyl-transferring) kinase; animal experiment; animal model; animal tissue; Article; carcinogenesis; cell membrane; cell migration; controlled study; enzyme activity; enzyme inhibition; gene overexpression; human; human tissue; in vitro study; male; mouse; nonhuman; priority journal; prostate cancer; protein binding; protein phosphorylation; protein protein interaction; signal transduction; tumor xenograft; U2OS cell line; upregulation; amino acid sequence; animal; antagonists and inhibitors; cell proliferation; chemistry; culture technique; disease course; drug screening; enzymology; epithelial mesenchymal transition; metabolism; molecular genetics; neoplasm; pathology; phosphorylation; prostate tumor; tumor cell line; Amino Acid Sequence; Animals; beta Catenin; Cell Culture Techniques; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Disease Progression; Epithelial-Mesenchymal Transition; Glycogen Synthase Kinase 3; Humans; Male; Mice; Molecular Sequence Data; Neoplasms; Peptides; Phosphorylation; Prostatic Neoplasms; Protein Binding; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays
Publisher
Nature Publishing Group
Type
journal article