Journal
BRITISH JOURNAL OF CANCER
Volume 108, Issue 12, Pages 2590-2600Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2013.160
Keywords
protein phosphatase type 2A; phosphorylation; dephosphorylation; AKT signalling; prostate cancer; PP2A subunits
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Funding
- Department of Defense [PC074289]
- National Institutes of Health [R01 CA138791]
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Background: Protein phosphatase 2A (PP2A) is a dephosphorylating enzyme, loss of which can contribute to prostate cancer (PCa) pathogenesis. The aim of this study was to analyse the transcriptional and translational expression patterns of individual subunits of the PP2A holoenzyme during PCa progression. Methods: Immunohistochemistry (IHC), western blot, and real-time PCR was performed on androgen-dependent (AD) and androgen-independent (AI) PCa cells, and benign and malignant prostate tissues for all the three PP2A (scaffold, regulatory, and catalytic) subunits. Mechanistic and functional studies were performed using various biochemical and cellular techniques. Results: Through immunohistochemical analysis we observed significantly reduced levels of PP2A-A and -B'gamma subunits (P<0.001 and P=0.0002) in PCa specimens compared with benign prostate. Contemporarily, there was no significant difference in PP2A-C subunit expression between benign and malignant tissues. Similar to the expression pattern observed in tissues, the endogenous levels of PP2A-A and B'gamma subunits were abrogated from the low metastatic to high metastatic and AD to AI cell line models, without any change in the catalytic subunit expression. Furthermore, using in vitro studies we demonstrated that PP2A-A alpha scaffold subunit has a role in dampening AKT, beta-catenin, and FAK (focal adhesion kinase) signalling. Conclusion: We conclude that loss of expression of scaffold and regulatory subunits of PP2A is responsible for its altered function during PCa pathogenesis.
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