title: 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".
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 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.
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Perico
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.|Current address: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Grasso
authors.affiliation: Department of Pathology and Diagnostics, Section of Pathology, University of Verona, Verona Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Department of Pathology and Diagnostics, Section of Pathology, University of Verona, Verona Italy.|Current address: Department of Pathology, Pederzoli Hospital, Verona, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Martignoni
authors.affiliation: Department of Pathology and Diagnostics, Section of Pathology, University of Verona, Verona Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Munari
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Moiso
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cestari
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine of Hannover, Hannover, Germany.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Colombatti
authors.affiliation: Department of Diagnostic Pathology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Dunia
authors.initials: D
authors.lastname: Ramarli
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494819:BAD protein, human; D051025:bcl-Associated Death Protein; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: BCAR1; PSMA; castration-resistant prostate adenocarcinoma; p130CAS; phospho-EGFR receptor