Journal article
Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells
Free radical biology & medicine, Vol.53(1), pp.95-108
07/01/2012
DOI: 10.1016/j.freeradbiomed.2012.03.024
PMCID: PMC3384717
PMID: 22561705
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, H2O2-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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► A novel p66Shc-reactive oxygen species (ROS)-Tyr-phosphorylation pathway mediates androgen action in PCa cells. ► Elevated p66Shc protein in PCa cells increases cell growth and tumorigenicity. ► p66Shc-ROS signaling downregulates protein Tyr phosphatase activity and activates the Tyr-phosphorylation pathway.
Details
- Title: Subtitle
- Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells
- Creators
- Suresh Veeramani - University of Nebraska Medical CenterYu-Wei Chou - University of Nebraska Medical CenterFrank C. Lin - University of Nebraska Medical CenterSakthivel Muniyan - University of Nebraska Medical CenterFen-Fen Lin - University of Nebraska Medical CenterSatyendra Kumar - University of Nebraska Medical CenterYan Xie - Creighton UniversitySubodh M. Lele - University of Nebraska Medical CenterYaping Tu - Creighton UniversityMing-Fong Lin - University of Nebraska Medical Center
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.53(1), pp.95-108
- DOI
- 10.1016/j.freeradbiomed.2012.03.024
- PMID
- 22561705
- PMCID
- PMC3384717
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 07/01/2012
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359683302771
Metrics
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