p66Shc longevity protein regulates the proliferation of human ovarian cancer cells

Sakthivel Muniyan, Yu Wei Chou, Te Jung Tsai, Paul G Thomes, Suresh Veeramani, Benedict B. Benigno, L. Deette Walker, John F. Mcdonald, Shafiq A. Khan, Fen Fen Lin, Subodh M Lele, Ming-Fong Lin

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)618-631
Number of pages14
JournalMolecular Carcinogenesis
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Ovarian Neoplasms
Proteins
Cell Proliferation
Phosphoric Monoester Hydrolases
Phosphorylation
MAP Kinase Signaling System
Growth
Small Interfering RNA
Transfection
Tyrosine
Oxidoreductases
Estrogens
Complementary DNA
Antioxidants
Cell Line

Keywords

  • ErbB-2 signaling
  • Estrogen
  • P66Shc
  • ROS
  • Tyrosine phosphatase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

p66Shc longevity protein regulates the proliferation of human ovarian cancer cells. / Muniyan, Sakthivel; Chou, Yu Wei; Tsai, Te Jung; Thomes, Paul G; Veeramani, Suresh; Benigno, Benedict B.; Walker, L. Deette; Mcdonald, John F.; Khan, Shafiq A.; Lin, Fen Fen; Lele, Subodh M; Lin, Ming-Fong.

In: Molecular Carcinogenesis, Vol. 54, No. 8, 01.08.2015, p. 618-631.

Research output: Contribution to journalArticle

Muniyan, S, Chou, YW, Tsai, TJ, Thomes, PG, Veeramani, S, Benigno, BB, Walker, LD, Mcdonald, JF, Khan, SA, Lin, FF, Lele, SM & Lin, M-F 2015, 'p66Shc longevity protein regulates the proliferation of human ovarian cancer cells', Molecular Carcinogenesis, vol. 54, no. 8, pp. 618-631. https://doi.org/10.1002/mc.22129
Muniyan, Sakthivel ; Chou, Yu Wei ; Tsai, Te Jung ; Thomes, Paul G ; Veeramani, Suresh ; Benigno, Benedict B. ; Walker, L. Deette ; Mcdonald, John F. ; Khan, Shafiq A. ; Lin, Fen Fen ; Lele, Subodh M ; Lin, Ming-Fong. / p66Shc longevity protein regulates the proliferation of human ovarian cancer cells. In: Molecular Carcinogenesis. 2015 ; Vol. 54, No. 8. pp. 618-631.
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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.",
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AU - Chou, Yu Wei

AU - Tsai, Te Jung

AU - Thomes, Paul G

AU - Veeramani, Suresh

AU - Benigno, Benedict B.

AU - Walker, L. Deette

AU - Mcdonald, John F.

AU - Khan, Shafiq A.

AU - Lin, Fen Fen

AU - Lele, Subodh M

AU - Lin, Ming-Fong

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