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.
Highlights
Prostate cancer (PCa) is the most common neoplasia and the third cause of cancer-related death in males in developed countries
Prostate Specific-Membrane Antigen (PSMA) cross-linking rescued LNCaP cells from apoptosis induced by serum starvation (Figure 1D)
PSMA, but not 7E11c-cross-linking alleviated apoptosis to 130±27% (p
Summary
Prostate cancer (PCa) is the most common neoplasia and the third cause of cancer-related death in males in developed countries. Increasing numbers of patients benefit from early diagnosis, yet, the prognosis of the 5-6% of patients bearing advanced, castration resistant PCa remains unsatisfactory due to the failure of chemoand radiotherapy regimens and the lack of early signatures of progression [1]. Pre-clinical and clinical evidence show that almost all PCa express PSMA, a transmembrane folate-hydrolase/carboxypeptidase involved in cellular nutrient uptake, which increases progressively in highgrade or castration resistant PCa in vivo [2, 3]. P130CAS expression was correlated with PCa progression in vivo [3, 7,8,9]
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