Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression
Rachana Patel, … , Owen J. Sansom, Hing Y. Leung
Rachana Patel, … , Owen J. Sansom, Hing Y. Leung
Published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1157-1175. https://doi.org/10.1172/JCI63672.
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Research Article Oncology

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

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.

Authors

Rachana Patel, Meiling Gao, Imran Ahmad, Janis Fleming, Lukram B. Singh, Taranjit Singh Rai, Arthur B. McKie, Morag Seywright, Robert J. Barnetson, Joanne Edwards, Owen J. Sansom, Hing Y. Leung

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Figure 1

SPRY2 KD decreases cell proliferation despite activation of mitogenic signaling.

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SPRY2 KD decreases cell proliferation despite activation of mitogenic si...
(A) Whole cell lysates (WCL) of Nsi VC and SPRY2 KD DU145 clones were analyzed by Western blot (WB). (B and C) WCLs of (B) MEFs and (C) prostatic tissue from mice as indicated were analyzed by Western blot (n = 3). (D and E) BrdU incorporation analysis on (D) DU145 and (E) MEFs with indicated genetic alterations (*P < 0.001, **P < 0.05; n = 3; analyzed by Mann-Whitney test). Data are presented as mean ± SEM. (F) Representative IHC images and quantification for Ki67 staining in prostates of indicated mice. Scale bars: 100 μm. Arrows indicate Ki67-positive nuclei. (*P < 0.01, **P < 0.001; number of mice analyzed = 5 analyzed by Dunnett’s multiple comparison test). Box and whisker plots show median (lines within boxes), interquartile range (bounds of boxes), and upper and lower range (whiskers). All the Western blots were quantified using ImageJ, and the values represent relative immunoreactivity of each protein normalized to respective loading control.