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Review
. 2016 Nov;173(21):3041-3079.
doi: 10.1111/bph.13576. Epub 2016 Sep 23.

The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease

James C Evans  1 , Meenakshi Malhotra  1 , John F Cryan  2 , Caitriona M O'Driscoll  3
Affiliations
Review

The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease

James C Evans et al. Br J Pharmacol. 2016 Nov.

Abstract

Prostate specific membrane antigen (PSMA) otherwise known as glutamate carboxypeptidase II (GCPII) is a membrane bound protein that is highly expressed in prostate cancer and in the neovasculature of a wide variety of tumours including glioblastomas, breast and bladder cancers. This protein is also involved in a variety of neurological diseases including schizophrenia and ALS. In recent years, there has been a surge in the development of both diagnostics and therapeutics that take advantage of the expression and activity of PSMA/GCPII. These include gene therapy, immunotherapy, chemotherapy and radiotherapy. In this review, we discuss the biological roles that PSMA/GCPII plays, both in normal and diseased tissues, and the current therapies exploiting its activity that are at the preclinical stage. We conclude by giving an expert opinion on the future direction of PSMA/GCPII based therapies and diagnostics and hurdles that need to be overcome to make them effective and viable.

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Figures

Figure 1
Figure 1
Schematic representation of PSMA/ GCPII transmembrane protein (homodimer). Adapted and modified from Bařinka et al., (2012).
Figure 2
Figure 2
Schematic representation of PSMA/GCPII regulation in prostate cancer cells Adapted and modified from Ghosh and Heston (2005a). Up‐regulation and down regulation of PSMA by Ca2 + ions and AR, respectively, is shown. (A) PSMA upregulation: NAAG and polyglutamated folates (PGF) are enzymically cleaved to folates and glutamates. The folates are taken up by the RFC or FBP present on the cell membrane. The glutamates activate the metabotropic glutamate receptors, which on activation, lead to the efflux of Cl− ions and influx of Ca2 + ions. Ca2 + ions further alter the expression of PSMA in two ways. First by activating the inactive transcription factor NFATc1 (which is a transcriptional activator of PSMA enhancer [PSME]), or cause activation of calpain, which cleaves FLNa. The truncated FLNa binds to AR and localizes to the nucleus and suppresses AR‐mediated transactivation. This effect leads to the upregulation of PSMA expression. (B) PSMA downregulation. Under normal conditions the cells do not express PSMA. Testosterone, an androgen is taken up by cells and is converted by 5‐α reductase enzyme to the active metabolite DHT. AR binds to the DHT and translocates it to the nucleus, where they activate the androgen‐regulated gene, thus down regulating PSMA expression. AR would also interact and sequester the transcription factor AP1 or tissue‐specific transcription factors, such as, SRY and SOX, which suppress the transcription of PSME.
Figure 3
Figure 3
Schematic representation of the role of PSMA/GCPII in the brain. PSMA/GCPII is expressed on the astrocytes and can lead the cells towards a neurodegenerative or a neuroprotective outcome. (A) in the neuroprotective role, to reduce the glutamate excitotoxicity, NAAG inhibitors can be used to competitively bind to the PSMA or to the glutamate receptor, avoiding the hydrolysis of NAAG into NAA and glutamate. Due to this effect, NAAG interacts with the metabotropic receptors on astrocytes, which leads to the production of growth factors and thus acts as a neuroprotective agent. NAAG and glutamate are also regularly recycled into the presynaptic neuron via G‐protein coupled pathway and glutamate‐glutamine pathway, respectively. (B) in the neurodegenerative role, NAAG, a neuropeptide released from the presynaptic neuron in the brain interacts with the PSMA/GCPII transmembrane protein. The interaction causes hydrolysis of NAAG into NAA and glutamate. The excess of glutamate leads to glutamate excitotoxicity in the synaptic cleft and further activates the ionotropic and metabotropic receptors on the post synaptic terminal of the neuron, leading to degeneration of cells.
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References

    1. Abdel‐Hadi M, Ismail Y, Younis L (2014). Prostate‐specific membrane antigen (PSMA) immunoexpression in the neovasculature of colorectal carcinoma in Egyptian patients. Pathol Res Pract 210: 759–763. - PubMed
    1. Abdolahi M, Shahbazi‐Gahrouei D, Laurent S, Sermeus C, Firozian F, Allen BJ et al. (2013). Synthesis and in vitro evaluation of MR molecular imaging probes using J591 mAb‐conjugated SPIONs for specific detection of prostate cancer. Contrast Media Mol Imaging 8: 175–184. - PubMed
    1. Afshar‐Oromieh A, Avtzi E, Giesel FL, Holland‐Letz T, Linhart HG, Eder M et al. (2015). The diagnostic value of PET/CT imaging with the 68Ga‐labelled PSMA ligand HBED‐CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 42: 197–209. - PMC - PubMed
    1. Afshar‐Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG et al. (2014). Comparison of PET imaging with a 68Ga‐labelled PSMA ligand and 18F‐choline‐based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 41: 11–20. - PMC - PubMed
    1. Ahmadzadehfar H, Rahbar K, Kürpig S, Bögemann M, Claesener M, Eppard E et al. (2015). Early side effects and first results of radioligand therapy with 177Lu‐DKFZ‐617 PSMA of castrate‐resistant metastatic prostate cancer: a two‐centre study. EJNMMI Res 5: 1–8. - PMC - PubMed

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