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 language | English (US) |
|---|---|
| Pages (from-to) | 1-14 |
| Number of pages | 14 |
| Journal | Cellular Signalling |
| Volume | 46 |
| DOIs | |
| State | Published - Jun 1 2018 |
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All Science Journal Classification (ASJC) codes
- Cell Biology
Cite this
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 journal › Article
}
TY - JOUR
T1 - p66Shc regulates migration of castration-resistant prostate cancer cells
AU - Ingersoll, Matthew A.
AU - Chou, Yu Wei
AU - Lin, Jamie S.
AU - Yuan, Ta Chun
AU - Miller, Dannah R.
AU - Xie, Yan
AU - Tu, Yaping
AU - Oberley-Deegan, Rebecca E.
AU - Batra, Surinder K.
AU - Lin, Ming Fong
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85042387227&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042387227&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2018.02.008
DO - 10.1016/j.cellsig.2018.02.008
M3 - Article
C2 - 29462661
AN - SCOPUS:85042387227
VL - 46
SP - 1
EP - 14
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
ER -