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”
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Maria Elisa Perico1,*, Silvia Grasso1,6,*, Matteo Brunelli2, Guido Martignoni2,7, Enrico Munari2, Enrico Moiso5, Giulio Fracasso1, Tiziana Cestari1, Hassan Y. Naim3, Vincenzo Bronte1, Marco Colombatti1, Dunia Ramarli4
1Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy
2Department of Pathology and Diagnostics, Section of Pathology, University of Verona, Verona Italy
3Department of Physiological Chemistry, University of Veterinary Medicine of Hannover, Hannover, Germany
4Department of Diagnostic Pathology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
5Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
6Current address: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
7Current address: Department of Pathology, Pederzoli Hospital, Verona, Italy
*These authors have contributed equally to this work
Dunia Ramarli, email: [email protected]
Keywords: PSMA, castration-resistant prostate adenocarcinoma, p130CAS, BCAR1, phospho-EGFR receptor
Received: June 29, 2016 Accepted: September 02, 2016 Published: October 03, 2016
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.
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