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Mar. Drugs 2015, 13(6), 3276-3286; doi:10.3390/md13063276

Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

1
Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain
2
Group of Cancer Biomarkers, Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, E-28040 Madrid, Spain
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Angela Capper
Received: 12 February 2015 / Accepted: 13 May 2015 / Published: 27 May 2015
(This article belongs to the Special Issue Okadaic Acid and Dinophysis Toxins)
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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. View Full-Text
Keywords: p-PP2A; CIP2A; okadaic acid; prostate cancer; therapy p-PP2A; CIP2A; okadaic acid; prostate cancer; therapy
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Cristóbal, I.; González-Alonso, P.; Daoud, L.; Solano, E.; Torrejón, B.; Manso, R.; Madoz-Gúrpide, J.; Rojo, F.; García-Foncillas, J. Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer. Mar. Drugs 2015, 13, 3276-3286.

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