The expression of Prostate Specific-Membrane Antigen (PSMA) increases in high-grade prostate carcinoma envisaging a role in growth and progression. We show here that clustering PSMA at LNCaP or PC3-PSMA cell membrane activates AKT and MAPK pathways thus promoting proliferation and survival. PSMA activity was dependent on the assembly of a macromolecular complex including filamin A, beta1 integrin, p130CAS, c-Src and EGFR. Within this complex beta1 integrin became activated thereby inducing a c-Src-dependent EGFR phosphorylation at Y1086 and Y1173 EGF-independent residues. Silencing or blocking experiments with drugs demonstrated that all the complex components were required for full PSMA-dependent promotion of cell growth and/or survival in 3D culture, but that p130CAS and EGFR exerted a major role. All PSMA complex components were found assembled in multiple samples of two high-grade prostate carcinomas and associated with EGFR phosphorylation at Y1086. The expression of p130CAS and pEGFRY1086 was thus analysed by tissue micro array in 16 castration-resistant prostate carcinomas selected from 309 carcinomas and stratified from GS 3+4 to GS 5+5. Patients with Gleason Score ≤5 resulted negative whereas those with GS≥5 expressed p130CAS and pEGFRY1086 in 75% and 60% of the cases, respectively.Collectively, our results demonstrate for the first time that PSMA recruits a functionally active complex which is present in high-grade patients. In addition, two components of this complex, p130CAS and the novel pEGFRY1086, correlate with progression in castration-resistant patients and could be therefore useful in therapeutic or surveillance strategies of these patients.
Oncotarget. 2016 [Epub ahead of print]
Maria Elisa Perico, Silvia Grasso, Matteo Brunelli, Guido Martignoni, Enrico Munari, Enrico Moiso, Giulio Fracasso, Tiziana Cestari, Hassan Y Naim, Vincenzo Bronte, Marco Colombatti, Dunia Ramarli
Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy., Department of Pathology and Diagnostics, Section of Pathology, University of Verona, Verona Italy., Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., Department of Physiological Chemistry, University of Veterinary Medicine of Hannover, Hannover, Germany., Department of Diagnostic Pathology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.