Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, N-acetyl-a-linked acidic dipeptidase I, or folate hydrolase, is a type II, 750-amino acid transmembrane protein (100-120 kDa). PSMA is anchored in the cell membrane of prostate epithelial cells and belongs to the M28 peptidase family. PSMA acts as a glutamate carboxypeptidase on various substrates, including the neuropeptide N-acetyl-L-aspartyl-L-glutamate and the nutrient folate. The PSMA protein has a unique 3-part structure: a 19-amino-acid internal portion, a 24-amino-acid transmembrane portion and a 707-amino-acid external portion. PSMA expression is regulated by the androgen receptor (AR). PSMA is considered to be the best-established target antigen in prostate cancer (PCa) because it is highly and specifically expressed on the surface of prostate tumor cells at all tumor stages.
Fig.1 The structure of PSMA. (Maurer, 2016)
PSMA can enzymatically hydrolyze glutamated folates producing glutamate and folates that can enter the cell through proton-coupled folate transporter (PCFT), folate receptor (FR) or reduced folate carrier (RFC). Once inside the cell, folate is again polyglutamated and used for polyamine synthesis, methylation reactions and the nucleotide synthesis required for cell proliferation. Activation of metabotropic glutamate receptor (mGluR) by glutamate induces the release of calcium and activates cell survival associated with the PI3K-Akt pathway. In the absence of PSMA, Integrin β (Iβ) and insulin-like growth factor I receptor (IGF-1R) interact intracellularly with a scaffold protein RACK1 leading to the activation of the MAPK pathway. This interaction is disrupted by PSMA, changing the pathway activation from MAPK to PI3K-Akt in a switch-like manner. PSMA expression is regulated by the AR. Dihydrotestosterone (DHT) is the physiological activator of AR. PSMA transcription is suppressed by AR after activation by DHT. It is possible that the “MAPK/PI3K-Akt switch” function of PSMA could help the PCa cells to try to survive castration when AR activation is suppressed.
Fig.2 Function and regulators of PSMA in PCa. (Hyvkk, 2021)
Studies suggest a role for PSMA as an important participant in multiple stages of PCa progression. PSMA is the most prominent PCa cell-surface biomarker because it is highly and specifically expressed on the surface of Pca cells at all tumor stages. However, PSMA is not specific to the prostate gland, and lower-level expression of PSMA is seen in the brain, kidneys and salivary glands. PSMA has been implicated a role in diseases, such as amyotrophic lateral sclerosis, schizophrenia, multiple sclerosis, inflammatory bowel disease and cancer (such as renal, bladder, gastric and colorectal cancer as well as Pca). PSMA expression is highly organ-specific and the level of PSMA expression in PCa cells is about 1000 times higher than the expression found in other tissues. In addition, the high expression of PSMA on PCa correlates inversely with survival and increases with tumor grade. The development of radiotracers that target PSMA now enables imaging and treatment of PCa. PSMA is an ideal target for developing small-molecule radiopharmaceuticals which typically show fast blood clearance and low background activity. PSMA has been used for the imaging of primary and metastatic PCa in patients with radiolabeled PSMA-targeting antibodies or, more recently, small molecules.
The current role of PSMA as a marker for PCa diagnosis, imaging and therapy, is the most active and attractive target in clinical research fields. Creative Biolabs offers a full set of PSMA assay portfolio services, such as cell proliferation and cytotoxicity assay (such as Alamar blue assay, MTT assay, and CCK8), apoptosis evaluation by TUNEL assay, cell adhesion assay, western blot analyses, immunoprecipitation, immunofluorescence and immunohistochemistry, and so on.
Creative Biolabs is an expert in providing a full variety of tumor marker assay services for our global clients. Through our assay development services, we are continuously adding to these offerings and customizing solutions for our customers. If you have any questions or demands, please feel free to contact us.
References
For Research Use Only | Not For Clinical Use
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