title: Lineage-specific growth inhibition of NK cell lines by FOXO3 in association with Akt activation status.
abstract: FOXO3 and PRDM1 are located on 6q21, one of the most frequently deleted regions among natural killer (NK) cell neoplasms. We previously demonstrated that forced expression of each gene suppresses the proliferation of NK cell lines with the 6q deletion. In this study, the forced expression of FOXO3 or PRDM1 was performed in various cell lines to clarify these suppressive effects. Forced expression of PRDM1 suppressed the proliferation of not only NK cell lines, but also other broad lineage cell lines. On the other hand, forced expression of FOXO3 was only effective on NK cell lines. FOXO3 functions as a transcriptional factor when it is localized in nuclei. Akt is known to induce cytoplasmic localization of FOXO3 as a result of phosphorylation. Transduced FOXO3 was predominantly localized in nuclei of NK cell lines, while it was localized in the cytoplasm of all non-NK cell lines. NK cell lines showed significantly lower Akt activity compared to other lineage cell lines. The low Akt activity and nucleic localization of FOXO3 in NK cell neoplasms seemed to cause NK cell-specific suppression. These findings indicate the "functional lineage specificity" of FOXO3 and the possibility for NK cell-specific gene therapy with minimal unexpected effects.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Kennosuke
authors.initials: K
authors.lastname: Karube
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Kotaro
authors.initials: K
authors.lastname: Arita
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.forename: Young-Hyeh
authors.initials: YH
authors.lastname: Ko
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
mesh_terms: D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000074462:Positive Regulatory Domain I-Binding Factor 1; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051057:Proto-Oncogene Proteins c-akt