Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer
Related Experiment Video
Updated: Apr 11, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Ion Cristóbal1, Paula González-Alonso2, Lina Daoud3
1Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain. ion.cristobal@fjd.es.
Abstract:
Protein phosphatase 2A (PP2A) is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa). However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients.
Insights
Protein phosphatase 2A (PP2A) activation suppresses prostate cancer (PCa) growth by inhibiting proliferation and prostasphere formation. PP2A inhibition correlates with advanced PCa, suggesting PP2A activators as a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Protein phosphatase 2A (PP2A) is a tumor suppressor complex implicated in prostate cancer (PCa).
- The therapeutic potential of targeting PP2A in PCa requires further elucidation.
- PP2A activity and its regulators are increasingly recognized as critical in cancer progression.
Purpose of the Study:
- To investigate the therapeutic efficacy of PP2A activators in prostate cancer.
- To determine the underlying molecular mechanisms of PP2A-mediated anti-cancer effects.
- To correlate PP2A activity and related protein levels with PCa patient outcomes.
Main Methods:
- Treatment of PC-3 and LNCaP cell lines with PP2A activators (forskolin, FTY720) and inhibitor (okadaic acid).
- Assessment of PP2A activity, cell proliferation, prostasphere formation, and signaling pathways (AKT, ERK).
- Analysis of PP2A phosphorylation, CIP2A, and SET protein levels in cell lines and PCa patient samples.
Main Results:
- Forskolin and FTY720 activated PP2A, reduced cell growth, and impaired prostasphere formation.
- PP2A activation altered AKT and ERK phosphorylation; FTY720 decreased CIP2A levels.
- Okadaic acid blocked PP2A activation, confirming PP2A-dependent anti-tumor effects.
- Elevated PP2A phosphorylation and SET/CIP2A expression correlated with high Gleason scores and metastasis in PCa patients.
Conclusions:
- PP2A inhibition may contribute to prostate cancer progression.
- PP2A-activating drugs show promise as a novel therapeutic strategy for PCa.
- Modulating PP2A activity represents a potential avenue for PCa treatment.
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