Dataset Information

Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model.

ABSTRACT:

Background

Emergence of castration-resistance in prostate cancer (PCa) is invariably associated with aggressive and metastatic disease. Previously, we reported promotion of castration-resistance upon downregulation of PPP2CA (encoding catalytic subunit of protein phosphatase 2A (PP2A), ?-isoform); however, its role in PCa growth and metastasis remained undetermined.

Methods

PPP2CA was overexpressed/silenced in PCa cells by stable transfection. Gene expression was examined by reverse transcription polymerase chain reaction, immunoblot and immunofluorescence analyses, and transcriptional activity measured by luciferase-based promoter-reporter assay. Effect on PCa phenotype was studied in vitro and in orthotopic mouse model, and immunohistochemical/histological analyses performed to assess proliferation/apoptosis and confirm metastatic lesions.

Results

An inverse association of PPP2CA expression was observed with epithelial-to-mesenchymal transition (EMT) and aggressive PCa phenotype. PPP2CA restoration resulted in decreased nuclear accumulation and transcriptional activity of ?-catenin/NF-?B, and restitution of their activity abrogated PPP2CA-induced EMT reversal and suppression of PCa invasiveness. Akt mediated PPP2CA loss-induced nuclear accumulation of ?-catenin/NF-?B through inactivation of Gsk3-? and I?B-?, respectively. Animal studies revealed a suppressive effect of PPP2CA expression on PCa growth and metastasis.

Conclusions

Our findings suggest that PPP2CA downregulation serves as a molecular link between gain of castration-resistance and aggressive PCa phenotype, and its restoration could be an effective preventive/therapeutic approach against the advanced disease.

SUBMITTER: Bhardwaj A

PROVIDER: S-EPMC3992501 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model.

Bhardwaj A A Singh S S Srivastava S K SK Arora S S Hyde S J SJ Andrews J J Grizzle W E WE Singh A P AP

British journal of cancer 20140318 8

<h4>Background</h4>Emergence of castration-resistance in prostate cancer (PCa) is invariably associated with aggressive and metastatic disease. Previously, we reported promotion of castration-resistance upon downregulation of PPP2CA (encoding catalytic subunit of protein phosphatase 2A (PP2A), α-isoform); however, its role in PCa growth and metastasis remained undetermined.<h4>Methods</h4>PPP2CA was overexpressed/silenced in PCa cells by stable transfection. Gene expression was examined by rever ...[more]

PMID: 24642616

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Dataset Information

Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model.

Background

Methods

Results

Conclusions

Publications

Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model.

Similar Datasets

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