Details

Autor(en) / Beteiligte

• 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

Titel

p66Shc regulates migration of castration-resistant prostate cancer cells

Ist Teil von

• Cellular signalling, 2018-06, Vol.46, p.1-14

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •p66Shc is elevated in prostate androgen-independent cell lines.•p66Shc, via ROS, promotes castration-resistant prostate cancer migration.•Through ROS, p66Shc activates ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2, and Rac1.•p66Shc promotes lamellipodia formation and migration through Rac1 activation.•p66Shc is a promising biomarker and therapeutic target for advanced prostate cancer.