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

• Published in: British journal of cancer Vol. 110; no. 8; pp. 2000 - 2010
• Main Authors: Bhardwaj, A, Singh, S, Srivastava, S K, Arora, S, Hyde, S J, Andrews, J, Grizzle, W E, Singh, A P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-04-2014; Nature Publishing Group
• Subjects: 692/699/67/1059/2326; 692/699/67/589/466; 692/699/67/68; Androgens; Animals; Antibodies; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Disease Models, Animal; Drug Resistance; Epidemiology; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genotype & phenotype; Humans; Male; Medical sciences; Metastasis; Mice; Molecular Medicine; Molecular Targeted Therapy; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Nephrology. Urinary tract diseases; Oncology; Phosphatase; Plasmids; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Phosphatase 2 - antagonists & inhibitors; Protein Phosphatase 2 - biosynthesis; Protein Phosphatase 2 - genetics; Signal Transduction; Translational Therapeutics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United States > US; prostate cancer; orthotopic mouse model; metastasis; EMT; Animal model; Prostate tumor; Urinary system disease; Orthotopic; Prostate disease; Prostate metastasis; Rodentia; Malignant tumor; PPP2CA; Vertebrata; Mammalia; Cancerology; Tumor growth; Restoration; Mouse; Reversibility; Epithelial mesenchymal transition; Male genital diseases; Prostate cancer; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.141

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),
α
-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
β
-catenin/NF-
κ
B, and restitution of their activity abrogated
PPP2CA
-induced EMT reversal and suppression of PCa invasiveness. Akt mediated
PPP2CA
loss-induced nuclear accumulation of
β
-catenin/NF-
κ
B through inactivation of Gsk3-
β
and I
κ
B-
α
, 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.