title: Proteomic identification of 14-3-3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells.
abstract: Despite advancements in multimodality chemotherapy, conventional cytotoxic treatments still remain ineffective for a subset of patients with aggressive metastatic or multifocal osteosarcoma. It has been shown that pERK1/2 inhibition enhances chemosensitivity to doxorubicin and promotes osteosarcoma cell death in vivo and in vitro. One of the pro-apoptotic mechanisms is upregulation of Bim by pERK1/2 inhibitors. To this end, we examined proteomic changes of 143B human osteosarcoma cells with and without treatment of PD98059, pERK1/2 inhibitor. Specifically, we identified 14-3-3ϵ protein as a potential mediator of Bim expression in response to inhibition of pERK1/2. We hypothesized that 14-3-3ϵ mediates upregulation of Bim expression after pERK1/2 inhibition. We examined the expression of Bim after silencing 14-3-3ϵ using siRNA. The 14-3-3ϵ gene silencing resulted in downregulation of Bim expression after PD98059 treatment. These data indicate that 14-3-3ϵ is required for Bim expression and that it has an anti-cancer effect under pERK1/2 inhibition in 143B cells. By playing an essential role upstream of Bim, 14-3-3ϵ may potentially be a coadjuvant factor synergizing the effect of pERK1/2 inhibitors in addition to conventional cytotoxic agents for more effective osteosarcoma treatments.
authors.affiliation: Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 650 West 168th Street, New York, New York, 10032; Gachon Medical Research Institute, Gil Medical Center, Gachon University, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, South Korea.
authors.forename: Kyung Ok
authors.initials: KO
authors.lastname: Kim
authors.forename: Anny C
authors.initials: AC
authors.lastname: Hsu
authors.forename: Heon Goo
authors.initials: HG
authors.lastname: Lee
authors.forename: Neel
authors.initials: N
authors.lastname: Patel
authors.forename: Chandhanarat
authors.initials: C
authors.lastname: Chandhanayingyong
authors.forename: Thomas
authors.initials: T
authors.lastname: Hickernell
authors.forename: Francis Young-In
authors.initials: FY
authors.lastname: Lee
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D012516:Osteosarcoma / Q000473:pathology / Q000503:physiopathology*; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D048948:14-3-3 Proteins; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D005419:Flavonoids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C482983:YWHAE protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: 14-3-3ϵ; Bim; osteosarcoma cells; pERK1/2; pro-apoptotic effect