V-ATPase-associated prorenin receptor is upregulated in prostate cancer after PTEN loss
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Amro H. Mohammad1,2, Sarah Assadian1,2, Frédéric Couture3, Karen J. Lefebvre1,2, Wissal El-Assaad1,2, Veronique Barrès4, Veronique Ouellet4, Pierre-Luc Boulay1,2, Jieyi Yang1,2, Mathieu Latour5, Luc Furic6,7,8, William Muller1,2, Nahum Sonenberg1,2, Anne-Marie Mes-Masson9, Fred Saad10, Robert Day3 and Jose G. Teodoro1,2
1 Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada
2 Department of Biochemistry, McGill University, Montréal, Québec, Canada
3 Institut de Pharmacologie de Sherbrooke, Department of Surgery and Urology, Université de Sherbrooke, Sherbrooke, Québec, Canada
4 Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Institut du Cancer de Montréal, Montréal, Québec, Canada
5 Department of Pathology, CHUM, Université de Montréal, Montréal, Québec, Canada
6 Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
7 Cancer Program, Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
8 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
9 Department of Medicine, Université de Montréal, Montréal, Québec, Canada
10 Department of Surgery, CHUM, Université de Montréal, Montréal, Québec, Canada
|Jose G. Teodoro,||email:||[email protected]|
Keywords: prostate cancer; PTEN; prorenin receptor; soluble prorenin receptor; V-ATPase complex
Received: March 12, 2019 Accepted: May 30, 2019 Published: August 13, 2019
Phosphatase and tensin homolog (PTEN) tumor suppressor protein loss is common in prostate cancer (PCa). PTEN loss increases PI3K/Akt signaling, which promotes cell growth and survival. To find secreted biomarkers of PTEN loss, a proteomic screen was used to compare secretomes of cells with and without PTEN expression. We showed that PTEN downregulates Prorenin Receptor (PRR) expression and secretion of soluble Prorenin Receptor (sPRR) in PCa cells and in mouse. PRR is an accessory protein required for assembly of the vacuolar ATPase (V-ATPase) complex. V-ATPase is required for lysosomal acidification, amino acid sensing, efficient mechanistic target of Rapamycin complex 1 (mTORC1) activation, and β-Catenin signaling. On PCa tissue microarrays, PRR expression displayed a positive correlation with Akt phosphorylation. Moreover, PRR expression was required for proliferation of PCa cells by maintaining V-ATPase function. Further, we provided evidence for a potential clinical role for PRR expression and sPRR concentration in differentiating low from high Gleason grade PCa. Overall, the current study unveils a mechanism by which PTEN can inhibit tumor growth. Lower levels of PRR result in attenuated V-ATPase activity and reduced PCa cell proliferation.
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