Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Patel, R. et al. (2013) Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. Journal of Clinical Investigation, 123(3), pp. 1157-1175. (doi: 10.1172/JCI63672)

Abstract

Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmad, Professor Imran and Leung, Professor Hing and Rai, Dr Taranjit and Edwards, Professor Joanne and Fleming, Ms Janice and Patel, Dr Rachana and Gao, Miss Meiling and Sansom, Professor Owen
• Authors: Patel, R., Gao, M., Ahmad, I., Fleming, J., Singh, L.B., Rai, T.S., McKie, A.B., Seywright, M., Barnetson, R.J., Edwards, J., Sansom, O.J., and Leung, H.Y.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238
• Published Online: 22 February 2013
• Copyright Holders: Copyright © 2013 American Society for Clinical Investigation
• First Published: First published in Journal of Clinical Investigation 123(3):1157-1175
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher