p66Shc regulates migration of castration-resistant prostate cancer cells

Matthew A. Ingersoll, Yu Wei Chou, Jamie S. Lin, Ta Chun Yuan, Dannah R. Miller, Yan Xie, Yaping Tu, Rebecca E. Oberley-Deegan, Surinder K. Batra, Ming Fong Lin

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Metastatic castration-resistant (CR) prostate cancer (PCa) is a lethal disease for which no effective treatment is currently available. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and is elevated in clinical PCa and multiple CR PCa cell lines. We hypothesize p66Shc also increases the migratory activity of PCa cells through ROS and investigate the associated mechanism. Using the transwell assay, our study reveals that the level of p66Shc protein correlates with cell migratory ability across several PCa cell lines. Furthermore, we show hydrogen peroxide treatment induces migration of PCa cells that express low levels of p66Shc in a dose-dependent manner, while antioxidants inhibit migration. Conversely, PCa cells that express high levels of endogenous p66Shc or by cDNA transfection possess increased cell migration which is mitigated upon p66Shc shRNA transfection or expression of oxidase-deficient dominant-negative p66Shc W134F mutant. Protein microarray and immunoblot analyses reveal multiple proteins, including ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2 and Rac1, are activated in p66Shc-elevated cells. Their involvement in PCa migration was examined using respective small-molecule inhibitors. The role of Rac1 was further validated using cDNA transfection and, significantly, p66Shc is found to promote lamellipodia formation through Rac1 activation. In summary, the results of our current studies clearly indicate p66Shc also regulates PCa cell migration through ROS-mediated activation of migration-associated proteins, notably Rac1.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalCellular Signalling
Volume46
DOIs
StatePublished - Jun 1 2018

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Castration
Prostatic Neoplasms
Transfection
Reactive Oxygen Species
Cell Movement
Oxidoreductases
rac1 GTP-Binding Protein
Complementary DNA
Cell Line
Protein Array Analysis
Pseudopodia
Hydrogen Peroxide
Small Interfering RNA
Androgens
Proteins
Antioxidants
Growth

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Ingersoll, M. A., Chou, Y. W., Lin, J. S., Yuan, T. C., Miller, D. R., Xie, Y., ... Lin, M. F. (2018). p66Shc regulates migration of castration-resistant prostate cancer cells. Cellular Signalling, 46, 1-14. https://doi.org/10.1016/j.cellsig.2018.02.008

p66Shc regulates migration of castration-resistant prostate cancer cells. / Ingersoll, Matthew A.; Chou, Yu Wei; Lin, Jamie S.; Yuan, Ta Chun; Miller, Dannah R.; Xie, Yan; Tu, Yaping; Oberley-Deegan, Rebecca E.; Batra, Surinder K.; Lin, Ming Fong.

In: Cellular Signalling, Vol. 46, 01.06.2018, p. 1-14.

Research output: Contribution to journalArticle

Ingersoll, MA, Chou, YW, Lin, JS, Yuan, TC, Miller, DR, Xie, Y, Tu, Y, Oberley-Deegan, RE, Batra, SK & Lin, MF 2018, 'p66Shc regulates migration of castration-resistant prostate cancer cells', Cellular Signalling, vol. 46, pp. 1-14. https://doi.org/10.1016/j.cellsig.2018.02.008
Ingersoll, Matthew A. ; Chou, Yu Wei ; Lin, Jamie S. ; Yuan, Ta Chun ; Miller, Dannah R. ; Xie, Yan ; Tu, Yaping ; Oberley-Deegan, Rebecca E. ; Batra, Surinder K. ; Lin, Ming Fong. / p66Shc regulates migration of castration-resistant prostate cancer cells. In: Cellular Signalling. 2018 ; Vol. 46. pp. 1-14.
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AU - Batra, Surinder K.

AU - Lin, Ming Fong

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AB - Metastatic castration-resistant (CR) prostate cancer (PCa) is a lethal disease for which no effective treatment is currently available. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and is elevated in clinical PCa and multiple CR PCa cell lines. We hypothesize p66Shc also increases the migratory activity of PCa cells through ROS and investigate the associated mechanism. Using the transwell assay, our study reveals that the level of p66Shc protein correlates with cell migratory ability across several PCa cell lines. Furthermore, we show hydrogen peroxide treatment induces migration of PCa cells that express low levels of p66Shc in a dose-dependent manner, while antioxidants inhibit migration. Conversely, PCa cells that express high levels of endogenous p66Shc or by cDNA transfection possess increased cell migration which is mitigated upon p66Shc shRNA transfection or expression of oxidase-deficient dominant-negative p66Shc W134F mutant. Protein microarray and immunoblot analyses reveal multiple proteins, including ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2 and Rac1, are activated in p66Shc-elevated cells. Their involvement in PCa migration was examined using respective small-molecule inhibitors. The role of Rac1 was further validated using cDNA transfection and, significantly, p66Shc is found to promote lamellipodia formation through Rac1 activation. In summary, the results of our current studies clearly indicate p66Shc also regulates PCa cell migration through ROS-mediated activation of migration-associated proteins, notably Rac1.

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