Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells. Academic Article uri icon

Overview

abstract

  • Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.

publication date

  • January 25, 2022

Research

keywords

  • Antigens, Surface
  • Glutamate Carboxypeptidase II
  • Glutamates
  • Lysine
  • Molecular Probes
  • Prostatic Neoplasms
  • Urea

Identity

PubMed Central ID

  • PMC8795759

Scopus Document Identifier

  • 85123349143

Digital Object Identifier (DOI)

  • 10.6084/m9.figshare.15160110.v2(Accessed12August2021)

PubMed ID

  • 35064078

Additional Document Info

volume

  • 119

issue

  • 4