title: p66Shc longevity protein regulates the proliferation of human ovarian cancer cells.
abstract: p66Shc functions as a longevity protein in murine and exhibits oxidase activity in regulating diverse biological activities. In this study, we investigated the role of p66Shc protein in regulating ovarian cancer (OCa) cell proliferation. Among three cell lines examined, the slowest growing OVCAR-3 cells have the lowest level of p66Shc protein. Transient transfection with p66Shc cDNA expression vector in OVCAR-3 cells increases cell proliferation. Conversely, knock-down of p66Shc by shRNA in rapidly growing SKOV-3 cells results in decreased cell growth. In estrogen (E2)-treated CaOV-3 cells, elevated p66Shc protein level correlates with ROS level, ErbB-2 and ERK/MAPK activation, and cell proliferation. Further, the E2-stimulated proliferation of CaOV-3 cells was blocked by antioxidants and ErbB-2 inhibitor. Additionally, in E2-stimulated cells, the tartrate-sensitive, but not the tartrate-resistant, phosphatase activity decreases; concurrently, the tyrosine phosphorylation of ErbB-2 increases. Conversely, inhibition of phosphatase activity by L(+)-tartrate treatment increases p66Shc protein level, ErbB-2 tyrosine phosphorylation, ERK/MAPK activation, and cell growth. Further, inhibition of the ERK/MAPK pathway by PD98059 blocks E2-induced ERK/MAPK activation and cell proliferation in CaOV-3 cells. Moreover, immunohistochemical analyses showed that the p66Shc protein level was significantly higher in cancerous cells than in noncancerous cells in archival OCa tissues (n = 76; P = 0.00037). These data collectively indicate that p66Shc protein plays a critical role in up-regulating OCa progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Muniyan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chou
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.|College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Te-Jung
authors.initials: TJ
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Paul
authors.initials: P
authors.lastname: Thomes
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Suresh
authors.initials: S
authors.lastname: Veeramani
authors.affiliation: Ovarian Cancer Institute, Atlanta, Georgia.
authors.forename: Benedict B
authors.initials: BB
authors.lastname: Benigno
authors.affiliation: Department of Biology, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: L DeEtte
authors.initials: LD
authors.lastname: Walker
authors.affiliation: Department of Biology, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: John F
authors.initials: JF
authors.lastname: McDonald
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia.
authors.forename: Shafiq A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Lin
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Subodh M
authors.initials: SM
authors.lastname: Lele
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.|Department of Surgery/Urology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.|Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.|College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015854:Up-Regulation
chemical_list: D004967:Estrogens; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C528024:SHC1 protein, human; C508053:ERBB2 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ErbB-2 signaling; ROS; estrogen; p66Shc; tyrosine phosphatase