Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells

Suresh Veeramani, Yu Wei Chou, Frank C. Lin, Sakthivel Muniyan, Fen Fen Lin, Satyendra Kumar, Yan Xie, Subodh M Lele, Yaping Tu, Ming-Fong Lin

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Steroid hormones exhibit diverse biological activities. Despite intensive studies on steroid function at the genomic level, their nongenomic actions remain an enigma. In this study, we investigated the role of reactive oxygen species (ROS) in androgen-stimulated prostate cancer (PCa) cell proliferation. In androgen-treated PCa cells, increased cell growth and ROS production correlated with elevated p66Shc protein, an authentic oxidase. This growth stimulation was blocked by antioxidants. Further, elevated expression of p66Shc protein by cDNA transfection encoding wild-type protein, but not a redox-deficient (W134F) mutant, was associated with increased PCa cell proliferation. Conversely, knockdown of p66Shc expression by shRNA resulted in diminished cell growth. Increased p66Shc expression in PCa cells enhanced their tumorigenicity in xenograft animals. Importantly, p66Shc protein level is higher in clinical prostate adenocarcinomas than in adjacent noncancerous cells. Expression of redox-deficient p66Shc mutant protein abolished androgen-stimulated cell growth. In androgen-treated, H 2O 2-treated, and p66Shc cDNA-transfected PCa cells, cellular prostatic acid phosphatase, an authentic tyrosine phosphatase, was inactivated by reversible oxidation; subsequently, ErbB-2 was activated by phosphorylation at tyrosine-1221/1222. These results together support the notion that androgens induce ROS production through the elevation of p66Shc protein, which inactivates tyrosine phosphatase activity for the activation of interacting tyrosine kinase, leading to increased cell proliferation and enhanced tumorigenicity. Our results thus suggest that p66Shc protein functions at the critical junction point between androgens and tyrosine phosphorylation signaling in human PCa cells.

Original languageEnglish (US)
Pages (from-to)95-108
Number of pages14
JournalFree Radical Biology and Medicine
Volume53
Issue number1
DOIs
StatePublished - Jul 1 2012

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Phosphorylation
Androgens
Tyrosine
Reactive Oxygen Species
Prostatic Neoplasms
Cells
Cell proliferation
Cell growth
Proteins
Phosphoric Monoester Hydrolases
Cell Proliferation
Growth
Complementary DNA
Steroid hormones
Oxidation-Reduction
Steroids
Mutant Proteins
Bioactivity
Heterografts
Protein-Tyrosine Kinases

Keywords

  • Androgen
  • Free radicals
  • Reactive oxygen species
  • Tyrosine phosphorylation
  • p66Shc

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells. / Veeramani, Suresh; Chou, Yu Wei; Lin, Frank C.; Muniyan, Sakthivel; Lin, Fen Fen; Kumar, Satyendra; Xie, Yan; Lele, Subodh M; Tu, Yaping; Lin, Ming-Fong.

In: Free Radical Biology and Medicine, Vol. 53, No. 1, 01.07.2012, p. 95-108.

Research output: Contribution to journalArticle

Veeramani, Suresh ; Chou, Yu Wei ; Lin, Frank C. ; Muniyan, Sakthivel ; Lin, Fen Fen ; Kumar, Satyendra ; Xie, Yan ; Lele, Subodh M ; Tu, Yaping ; Lin, Ming-Fong. / Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells. In: Free Radical Biology and Medicine. 2012 ; Vol. 53, No. 1. pp. 95-108.
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AU - Kumar, Satyendra

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AB - Steroid hormones exhibit diverse biological activities. Despite intensive studies on steroid function at the genomic level, their nongenomic actions remain an enigma. In this study, we investigated the role of reactive oxygen species (ROS) in androgen-stimulated prostate cancer (PCa) cell proliferation. In androgen-treated PCa cells, increased cell growth and ROS production correlated with elevated p66Shc protein, an authentic oxidase. This growth stimulation was blocked by antioxidants. Further, elevated expression of p66Shc protein by cDNA transfection encoding wild-type protein, but not a redox-deficient (W134F) mutant, was associated with increased PCa cell proliferation. Conversely, knockdown of p66Shc expression by shRNA resulted in diminished cell growth. Increased p66Shc expression in PCa cells enhanced their tumorigenicity in xenograft animals. Importantly, p66Shc protein level is higher in clinical prostate adenocarcinomas than in adjacent noncancerous cells. Expression of redox-deficient p66Shc mutant protein abolished androgen-stimulated cell growth. In androgen-treated, H 2O 2-treated, and p66Shc cDNA-transfected PCa cells, cellular prostatic acid phosphatase, an authentic tyrosine phosphatase, was inactivated by reversible oxidation; subsequently, ErbB-2 was activated by phosphorylation at tyrosine-1221/1222. These results together support the notion that androgens induce ROS production through the elevation of p66Shc protein, which inactivates tyrosine phosphatase activity for the activation of interacting tyrosine kinase, leading to increased cell proliferation and enhanced tumorigenicity. Our results thus suggest that p66Shc protein functions at the critical junction point between androgens and tyrosine phosphorylation signaling in human PCa cells.

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