Journal article
p66Shc longevity protein regulates the proliferation of human ovarian cancer cells
Molecular carcinogenesis, Vol.54(8), pp.618-631
08/2015
DOI: 10.1002/mc.22129
PMCID: PMC4117819
PMID: 24395385
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.
Details
- Title: Subtitle
- p66Shc longevity protein regulates the proliferation of human ovarian cancer cells
- Creators
- Sakthivel Muniyan - University of Nebraska Medical CenterYu-Wei Chou - University of Nebraska Medical CenterTe-Jung Tsai - University of Nebraska Medical CenterPaul Thomes - University of Nebraska Medical CenterSuresh Veeramani - University of Nebraska Medical CenterBenedict B Benigno - Ovarian Cancer InstituteL DeEtte Walker - Georgia Institute of TechnologyJohn F McDonald - Georgia Institute of TechnologyShafiq A Khan - Clark Atlanta UniversityFen-Fen Lin - University of Nebraska Medical CenterSubodh M Lele - University of Nebraska Medical CenterMing-Fong Lin - University of Nebraska Medical Center
- Resource Type
- Journal article
- Publication Details
- Molecular carcinogenesis, Vol.54(8), pp.618-631
- DOI
- 10.1002/mc.22129
- PMID
- 24395385
- PMCID
- PMC4117819
- ISSN
- 0899-1987
- eISSN
- 1098-2744
- Grant note
- R01 CA88184 / NCI NIH HHS R01 CA088184 / NCI NIH HHS G12 RR003062 / NCRR NIH HHS G12 MD007590 / NIMHD NIH HHS
- Language
- English
- Date published
- 08/2015
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359818702771
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