Prostate-specific membrane antigen (PSMA) assembles a macromolecular complex regulating growth and survival of prostate cancer cells "in vitro" and correlating with progression "in vivo"

// Maria Elisa Perico 1, * , Silvia Grasso 1, 6, * , Matteo Brunelli 2 , Guido Martignoni 2, 7 , Enrico Munari 2 , Enrico Moiso 5 , Giulio Fracasso 1 , Tiziana Cestari 1 , Hassan Y. Naim 3 , Vincenzo Bronte 1 , Marco Colombatti 1 , Dunia Ramarli 4 1 Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy 2 Department of Pathology and Diagnostics, Section of Pathology, University of Verona, Verona Italy 3 Department of Physiological Chemistry, University of Veterinary Medicine of Hannover, Hannover, Germany 4 Department of Diagnostic Pathology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy 5 Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy 6 Current address: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy 7 Current address: Department of Pathology, Pederzoli Hospital, Verona, Italy * These authors have contributed equally to this work Correspondence to: Dunia Ramarli, email: dunia.ramarli@ospedaleuniverona.it Keywords: PSMA, castration-resistant prostate adenocarcinoma, p130CAS, BCAR1, phospho-EGFR receptor Received: June 29, 2016      Accepted: September 02, 2016      Published: October 03, 2016 ABSTRACT 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 Y 1086 and Y 1173 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 Y 1086 . The expression of p130CAS and pEGFR Y1086 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 pEGFR Y1086 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 pEGFR Y1086 , correlate with progression in castration-resistant patients and could be therefore useful in therapeutic or surveillance strategies of these patients.